Ciscar, M.
Trinidad, E.M.
Perez-Chacon, G.
Alsaleem, M.
Jimenez, M.
Jimenez-Santos, M.J.
Perez-Montoyo, H.
Sanz-Moreno, A.
Vethencourt, A.
Toss, M.
Petit, A.
Soler-Monso, M.T.
Lopez, V.
Gomez-Miragaya, J.
Gomez-Aleza, C.
Dobrolecki, L.E.
Lewis, M.T.
Bruna, A.
Mouron, S.
Quintela-Fandino, M.
Al-Shahrour, F.
Martinez-Aranda, A.
Sierra, A.
Green, A.R.
Rakha, E.
Gonzalez-Suarez, E.
(2023). RANK is a poor prognosis marker and a therapeutic target in ER-negative postmenopausal breast cancer. Embo mol med,
Vol.15
(4),
p. e16715.
show abstract
full text
Despite strong preclinical data, the therapeutic benefit of the RANKL inhibitor, denosumab, in breast cancer patients, beyond the bone, is unclear. Aiming to select patients who may benefit from denosumab, we hereby analyzed RANK and RANKL protein expression in more than 2,000 breast tumors (777 estrogen receptor-negative, ER- ) from four independent cohorts. RANK protein expression was more frequent in ER- tumors, where it associated with poor outcome and poor response to chemotherapy. In ER- breast cancer patient-derived orthoxenografts (PDXs), RANKL inhibition reduced tumor cell proliferation and stemness, regulated tumor immunity and metabolism, and improved response to chemotherapy. Intriguingly, tumor RANK protein expression associated with poor prognosis in postmenopausal breast cancer patients, activation of NFKB signaling, and modulation of immune and metabolic pathways, suggesting that RANK signaling increases after menopause. Our results demonstrate that RANK protein expression is an independent biomarker of poor prognosis in postmenopausal and ER- breast cancer patients and support the therapeutic benefit of RANK pathway inhibitors, such as denosumab, in breast cancer patients with RANK+ ER- tumors after menopause..
Dinami, R.
Pompili, L.
Petti, E.
Porru, M.
D'Angelo, C.
Di Vito, S.
Rizzo, A.
Campani, V.
De Rosa, G.
Bruna, A.
Serra, V.
Mano, M.
Giacca, M.
Leonetti, C.
Ciliberto, G.
Tarsounas, M.
Stoppacciaro, A.
Schoeftner, S.
Biroccio, A.
(2023). MiR-182-3p targets TRF2 and impairs tumor growth of triple-negative breast cancer. Embo mol med,
Vol.15
(1),
p. e16033.
show abstract
The telomeric repeat-binding factor 2 (TRF2) is a telomere-capping protein that plays a key role in the maintenance of telomere structure and function. It is highly expressed in different cancer types, and it contributes to cancer progression. To date, anti-cancer strategies to target TRF2 remain a challenge. Here, we developed a miRNA-based approach to reduce TRF2 expression. By performing a high-throughput luciferase screening of 54 candidate miRNAs, we identified miR-182-3p as a specific and efficient post-transcriptional regulator of TRF2. Ectopic expression of miR-182-3p drastically reduced TRF2 protein levels in a panel of telomerase- or alternative lengthening of telomeres (ALT)-positive cancer cell lines. Moreover, miR-182-3p induced DNA damage at telomeric and pericentromeric sites, eventually leading to strong apoptosis activation. We also observed that treatment with lipid nanoparticles (LNPs) containing miR-182-3p impaired tumor growth in triple-negative breast cancer (TNBC) models, including patient-derived tumor xenografts (PDTXs), without affecting mouse survival or tissue function. Finally, LNPs-miR-182-3p were able to cross the blood-brain barrier and reduce intracranial tumors representing a possible therapeutic option for metastatic brain lesions..
Kreuzaler, P.
Inglese, P.
Ghanate, A.
Gjelaj, E.
Wu, V.
Panina, Y.
Mendez-Lucas, A.
MacLachlan, C.
Patani, N.
Hubert, C.B.
Huang, H.
Greenidge, G.
Rueda, O.M.
Taylor, A.J.
Karali, E.
Kazanc, E.
Spicer, A.
Dexter, A.
Lin, W.
Thompson, D.
Silva Dos Santos, M.
Calvani, E.
Legrave, N.
Ellis, J.K.
Greenwood, W.
Green, M.
Nye, E.
Still, E.
CRUK Rosetta Grand Challenge Consortium,
Barry, S.
Goodwin, R.J.
Bruna, A.
Caldas, C.
MacRae, J.
de Carvalho, L.P.
Poulogiannis, G.
McMahon, G.
Takats, Z.
Bunch, J.
Yuneva, M.
(2023). Vitamin B5 supports MYC oncogenic metabolism and tumor progression in breast cancer. Nat metab,
Vol.5
(11),
pp. 1870-1886.
show abstract
full text
Tumors are intrinsically heterogeneous and it is well established that this directs their evolution, hinders their classification and frustrates therapy1-3. Consequently, spatially resolved omics-level analyses are gaining traction4-9. Despite considerable therapeutic interest, tumor metabolism has been lagging behind this development and there is a paucity of data regarding its spatial organization. To address this shortcoming, we set out to study the local metabolic effects of the oncogene c-MYC, a pleiotropic transcription factor that accumulates with tumor progression and influences metabolism10,11. Through correlative mass spectrometry imaging, we show that pantothenic acid (vitamin B5) associates with MYC-high areas within both human and murine mammary tumors, where its conversion to coenzyme A fuels Krebs cycle activity. Mechanistically, we show that this is accomplished by MYC-mediated upregulation of its multivitamin transporter SLC5A6. Notably, we show that SLC5A6 over-expression alone can induce increased cell growth and a shift toward biosynthesis, whereas conversely, dietary restriction of pantothenic acid leads to a reversal of many MYC-mediated metabolic changes and results in hampered tumor growth. Our work thus establishes the availability of vitamins and cofactors as a potential bottleneck in tumor progression, which can be exploited therapeutically. Overall, we show that a spatial understanding of local metabolism facilitates the identification of clinically relevant, tractable metabolic targets..
Cannell, I.G.
Sawicka, K.
Pearsall, I.
Wild, S.A.
Deighton, L.
Pearsall, S.M.
Lerda, G.
Joud, F.
Khan, S.
Bruna, A.
Simpson, K.L.
Mulvey, C.M.
Nugent, F.
Qosaj, F.
Bressan, D.
CRUK IMAXT Grand Challenge Team,
Dive, C.
Caldas, C.
Hannon, G.J.
(2023). FOXC2 promotes vasculogenic mimicry and resistance to anti-angiogenic therapy. Cell rep,
Vol.42
(8),
p. 112791.
show abstract
Vasculogenic mimicry (VM) describes the formation of pseudo blood vessels constructed of tumor cells that have acquired endothelial-like properties. VM channels endow the tumor with a tumor-derived vascular system that directly connects to host blood vessels, and their presence is generally associated with poor patient prognosis. Here we show that the transcription factor, Foxc2, promotes VM in diverse solid tumor types by driving ectopic expression of endothelial genes in tumor cells, a process that is stimulated by hypoxia. VM-proficient tumors are resistant to anti-angiogenic therapy, and suppression of Foxc2 augments response. This work establishes co-option of an embryonic endothelial transcription factor by tumor cells as a key mechanism driving VM proclivity and motivates the search for VM-inhibitory agents that could form the basis of combination therapies with anti-angiogenics..
Palafox, M.
Monserrat, L.
Bellet, M.
Villacampa, G.
Gonzalez-Perez, A.
Oliveira, M.
Brasó-Maristany, F.
Ibrahimi, N.
Kannan, S.
Mina, L.
Herrera-Abreu, M.T.
Òdena, A.
Sánchez-Guixé, M.
Capelán, M.
Azaro, A.
Bruna, A.
Rodríguez, O.
Guzmán, M.
Grueso, J.
Viaplana, C.
Hernández, J.
Su, F.
Lin, K.
Clarke, R.B.
Caldas, C.
Arribas, J.
Michiels, S.
García-Sanz, A.
Turner, N.C.
Prat, A.
Nuciforo, P.
Dienstmann, R.
Verma, C.S.
Lopez-Bigas, N.
Scaltriti, M.
Arnedos, M.
Saura, C.
Serra, V.
(2022). High p16 expression and heterozygous RB1 loss are biomarkers for CDK4/6 inhibitor resistance in ER+ breast cancer. Nat commun,
Vol.13
(1),
p. 5258.
show abstract
full text
CDK4/6 inhibitors combined with endocrine therapy have demonstrated higher antitumor activity than endocrine therapy alone for the treatment of advanced estrogen receptor-positive breast cancer. Some of these tumors are de novo resistant to CDK4/6 inhibitors and others develop acquired resistance. Here, we show that p16 overexpression is associated with reduced antitumor activity of CDK4/6 inhibitors in patient-derived xenografts (n = 37) and estrogen receptor-positive breast cancer cell lines, as well as reduced response of early and advanced breast cancer patients to CDK4/6 inhibitors (n = 89). We also identified heterozygous RB1 loss as biomarker of acquired resistance and poor clinical outcome. Combination of the CDK4/6 inhibitor ribociclib with the PI3K inhibitor alpelisib showed antitumor activity in estrogen receptor-positive non-basal-like breast cancer patient-derived xenografts, independently of PIK3CA, ESR1 or RB1 mutation, also in drug de-escalation experiments or omitting endocrine therapy. Our results offer insights into predicting primary/acquired resistance to CDK4/6 inhibitors and post-progression therapeutic strategies..
Groelly, F.J.
Porru, M.
Zimmer, J.
Benainous, H.
De Visser, Y.
Kosova, A.A.
Di Vito, S.
Serra, V.
Ryan, A.
Leonetti, C.
Bruna, A.
Biroccio, A.
Tarsounas, M.
(2022). Anti-tumoural activity of the G-quadruplex ligand pyridostatin against BRCA1/2-deficient tumours. Embo mol med,
Vol.14
(3),
p. e14501.
show abstract
full text
The cells with compromised BRCA1 or BRCA2 (BRCA1/2) function accumulate stalled replication forks, which leads to replication-associated DNA damage and genomic instability, a signature of BRCA1/2-mutated tumours. Targeted therapies against BRCA1/2-mutated tumours exploit this vulnerability by introducing additional DNA lesions. Because homologous recombination (HR) repair is abrogated in the absence of BRCA1 or BRCA2, these lesions are specifically lethal to tumour cells, but not to the healthy tissue. Ligands that bind and stabilise G-quadruplexes (G4s) have recently emerged as a class of compounds that selectively eliminate the cells and tumours lacking BRCA1 or BRCA2. Pyridostatin is a small molecule that binds G4s and is specifically toxic to BRCA1/2-deficient cells in vitro. However, its in vivo potential has not yet been evaluated. Here, we demonstrate that pyridostatin exhibits a high specific activity against BRCA1/2-deficient tumours, including patient-derived xenograft tumours that have acquired PARP inhibitor (PARPi) resistance. Mechanistically, we demonstrate that pyridostatin disrupts replication leading to DNA double-stranded breaks (DSBs) that can be repaired in the absence of BRCA1/2 by canonical non-homologous end joining (C-NHEJ). Consistent with this, chemical inhibitors of DNA-PKcs, a core component of C-NHEJ kinase activity, act synergistically with pyridostatin in eliminating BRCA1/2-deficient cells and tumours. Furthermore, we demonstrate that pyridostatin triggers cGAS/STING-dependent innate immune responses when BRCA1 or BRCA2 is abrogated. Paclitaxel, a drug routinely used in cancer chemotherapy, potentiates the in vivo toxicity of pyridostatin. Overall, our results demonstrate that pyridostatin is a compound suitable for further therapeutic development, alone or in combination with paclitaxel and DNA-PKcs inhibitors, for the benefit of cancer patients carrying BRCA1/2 mutations..
Serra, V.
Wang, A.T.
Castroviejo-Bermejo, M.
Polanska, U.M.
Palafox, M.
Herencia-Ropero, A.
Jones, G.N.
Lai, Z.
Armenia, J.
Michopoulos, F.
Llop-Guevara, A.
Brough, R.
Gulati, A.
Pettitt, S.J.
Bulusu, K.C.
Nikkilä, J.
Wilson, Z.
Hughes, A.
Wijnhoven, P.W.
Ahmed, A.
Bruna, A.
Gris-Oliver, A.
Guzman, M.
Rodríguez, O.
Grueso, J.
Arribas, J.
Cortés, J.
Saura, C.
Lau, A.
Critchlow, S.
Dougherty, B.
Caldas, C.
Mills, G.B.
Barrett, J.C.
Forment, J.V.
Cadogan, E.
Lord, C.J.
Cruz, C.
Balmaña, J.
O'Connor, M.J.
(2022). Identification of a Molecularly-Defined Subset of Breast and Ovarian Cancer Models that Respond to WEE1 or ATR Inhibition, Overcoming PARP Inhibitor Resistance. Clin cancer res,
Vol.28
(20),
pp. 4536-4550.
show abstract
full text
PURPOSE: PARP inhibitors (PARPi) induce synthetic lethality in homologous recombination repair (HRR)-deficient tumors and are used to treat breast, ovarian, pancreatic, and prostate cancers. Multiple PARPi resistance mechanisms exist, most resulting in restoration of HRR and protection of stalled replication forks. ATR inhibition was highlighted as a unique approach to reverse both aspects of resistance. Recently, however, a PARPi/WEE1 inhibitor (WEE1i) combination demonstrated enhanced antitumor activity associated with the induction of replication stress, suggesting another approach to tackling PARPi resistance. EXPERIMENTAL DESIGN: We analyzed breast and ovarian patient-derived xenoimplant models resistant to PARPi to quantify WEE1i and ATR inhibitor (ATRi) responses as single agents and in combination with PARPi. Biomarker analysis was conducted at the genetic and protein level. Metabolite analysis by mass spectrometry and nucleoside rescue experiments ex vivo were also conducted in patient-derived models. RESULTS: Although WEE1i response was linked to markers of replication stress, including STK11/RB1 and phospho-RPA, ATRi response associated with ATM mutation. When combined with olaparib, WEE1i could be differentiated from the ATRi/olaparib combination, providing distinct therapeutic strategies to overcome PARPi resistance by targeting the replication stress response. Mechanistically, WEE1i sensitivity was associated with shortage of the dNTP pool and a concomitant increase in replication stress. CONCLUSIONS: Targeting the replication stress response is a valid therapeutic option to overcome PARPi resistance including tumors without an underlying HRR deficiency. These preclinical insights are now being tested in several clinical trials where the PARPi is administered with either the WEE1i or the ATRi..
Gris-Oliver, A.
Ibrahim, Y.H.
Rivas, M.A.
García-García, C.
Sánchez-Guixé, M.
Ruiz-Pace, F.
Viaplana, C.
Pérez-García, J.M.
Llombart-Cussac, A.
Grueso, J.
Parés, M.
Guzmán, M.
Rodríguez, O.
Anton, P.
Cozar, P.
Calvo, M.T.
Bruna, A.
Arribas, J.
Caldas, C.
Dienstmann, R.
Nuciforo, P.
Oliveira, M.
Cortés, J.
Serra, V.
(2021). PI3K activation promotes resistance to eribulin in HER2-negative breast cancer. Br j cancer,
Vol.124
(9),
pp. 1581-1591.
show abstract
BACKGROUND: Eribulin is a microtubule-targeting agent approved for the treatment of advanced or metastatic breast cancer (BC) previously treated with anthracycline- and taxane-based regimens. PIK3CA mutation is associated with worse response to chemotherapy in oestrogen receptor-positive (ER+)/human epidermal growth factor receptor 2-negative (HER2-) metastatic BC. We aimed to evaluate the role of phosphoinositide 3-kinase (PI3K)/AKT pathway mutations in eribulin resistance. METHODS: Resistance to eribulin was evaluated in HER2- BC cell lines and patient-derived tumour xenografts, and correlated with a mutation in the PI3K/AKT pathway. RESULTS: Eleven out of 23 HER2- BC xenografts treated with eribulin exhibited disease progression. No correlation with ER status was detected. Among the resistant models, 64% carried mutations in PIK3CA, PIK3R1 or AKT1, but only 17% among the sensitive xenografts (P = 0.036). We observed that eribulin treatment induced AKT phosphorylation in vitro and in patient tumours. In agreement, the addition of PI3K inhibitors reversed primary and acquired resistance to eribulin in xenograft models, regardless of the genetic alterations in PI3K/AKT pathway or ER status. Mechanistically, PI3K blockade reduced p21 levels likely enabling apoptosis, thus sensitising to eribulin treatment. CONCLUSIONS: PI3K pathway activation induces primary resistance or early adaptation to eribulin, supporting the combination of PI3K inhibitors and eribulin for the treatment of HER2- BC patients..
Batra, R.N.
Lifshitz, A.
Vidakovic, A.T.
Chin, S.-.
Sati-Batra, A.
Sammut, S.-.
Provenzano, E.
Ali, H.R.
Dariush, A.
Bruna, A.
Murphy, L.
Purushotham, A.
Ellis, I.
Green, A.
Garrett-Bakelman, F.E.
Mason, C.
Melnick, A.
Aparicio, S.A.
Rueda, O.M.
Tanay, A.
Caldas, C.
(2021). DNA methylation landscapes of 1538 breast cancers reveal a replication-linked clock, epigenomic instability and cis-regulation. Nat commun,
Vol.12
(1),
p. 5406.
show abstract
DNA methylation is aberrant in cancer, but the dynamics, regulatory role and clinical implications of such epigenetic changes are still poorly understood. Here, reduced representation bisulfite sequencing (RRBS) profiles of 1538 breast tumors and 244 normal breast tissues from the METABRIC cohort are reported, facilitating detailed analysis of DNA methylation within a rich context of genomic, transcriptional, and clinical data. Tumor methylation from immune and stromal signatures are deconvoluted leading to the discovery of a tumor replication-linked clock with genome-wide methylation loss in non-CpG island sites. Unexpectedly, methylation in most tumor CpG islands follows two replication-independent processes of gain (MG) or loss (ML) that we term epigenomic instability. Epigenomic instability is correlated with tumor grade and stage, TP53 mutations and poorer prognosis. After controlling for these global trans-acting trends, as well as for X-linked dosage compensation effects, cis-specific methylation and expression correlations are uncovered at hundreds of promoters and over a thousand distal elements. Some of these targeted known tumor suppressors and oncogenes. In conclusion, this study demonstrates that global epigenetic instability can erode cancer methylomes and expose them to localized methylation aberrations in-cis resulting in transcriptional changes seen in tumors..
Ros, S.
Wright, A.J.
Bruna, A.
Caldas, C.
Brindle, K.M.
(2021). Metabolic imaging with hyperpolarized [1-13C] pyruvate in patient-derived preclinical mouse models of breast cancer. Star protoc,
Vol.2
(3),
p. 100608.
show abstract
full text
13C nuclear spin hyperpolarization can increase the sensitivity of detection in an MRI experiment by more than 10,000-fold. 13C magnetic resonance spectroscopic imaging (MRSI) of hyperpolarized 13C label exchange between injected [1-13C]pyruvate and the endogenous tumor lactate pool can be used clinically to assess tumor grade and response to treatment. We describe here an experimental protocol for using this technique in patient-derived and established cell line xenograft models of breast cancer in the mouse. For complete details on the use and execution of this protocol, please refer to Ros et al. (2020)..
Tognetti, M.
Gabor, A.
Yang, M.
Cappelletti, V.
Windhager, J.
Rueda, O.M.
Charmpi, K.
Esmaeilishirazifard, E.
Bruna, A.
de Souza, N.
Caldas, C.
Beyer, A.
Picotti, P.
Saez-Rodriguez, J.
Bodenmiller, B.
(2021). Deciphering the signaling network of breast cancer improves drug sensitivity prediction. Cell syst,
Vol.12
(5),
pp. 401-418.e12.
show abstract
full text
One goal of precision medicine is to tailor effective treatments to patients' specific molecular markers of disease. Here, we used mass cytometry to characterize the single-cell signaling landscapes of 62 breast cancer cell lines and five lines from healthy tissue. We quantified 34 markers in each cell line upon stimulation by the growth factor EGF in the presence or absence of five kinase inhibitors. These data-on more than 80 million single cells from 4,000 conditions-were used to fit mechanistic signaling network models that provide insight into how cancer cells process information. Our dynamic single-cell-based models accurately predicted drug sensitivity and identified genomic features associated with drug sensitivity, including a missense mutation in DDIT3 predictive of PI3K-inhibition sensitivity. We observed similar trends in genotype-drug sensitivity associations in patient-derived xenograft mouse models. This work provides proof of principle that patient-specific single-cell measurements and modeling could inform effective precision medicine strategies..
Nguyen, L.C.
Naulaerts, S.
Bruna, A.
Ghislat, G.
Ballester, P.J.
(2021). Predicting Cancer Drug Response In Vivo by Learning an Optimal Feature Selection of Tumour Molecular Profiles. Biomedicines,
Vol.9
(10).
show abstract
(1) Background: Inter-tumour heterogeneity is one of cancer's most fundamental features. Patient stratification based on drug response prediction is hence needed for effective anti-cancer therapy. However, single-gene markers of response are rare and/or may fail to achieve a significant impact in the clinic. Machine Learning (ML) is emerging as a particularly promising complementary approach to precision oncology. (2) Methods: Here we leverage comprehensive Patient-Derived Xenograft (PDX) pharmacogenomic data sets with dimensionality-reducing ML algorithms with this purpose. (3) Results: Combining multiple gene alterations via ML leads to better discrimination between sensitive and resistant PDXs in 19 of the 26 analysed cases. Highly predictive ML models employing concise gene lists were found for three cases: paclitaxel (breast cancer), binimetinib (breast cancer) and cetuximab (colorectal cancer). Interestingly, each of these multi-gene ML models identifies some treatment-responsive PDXs not harbouring the best actionable mutation for that case. Thus, ML multi-gene predictors generally have much fewer false negatives than the corresponding single-gene marker. (4) Conclusions: As PDXs often recapitulate clinical outcomes, these results suggest that many more patients could benefit from precision oncology if ML algorithms were also applied to existing clinical pharmacogenomics data, especially those algorithms generating classifiers combining data-selected gene alterations..
Tucker, E.R.
George, S.
Angelini, P.
Bruna, A.
Chesler, L.
(2021). The Promise of Patient-Derived Preclinical Models to Accelerate the Implementation of Personalised Medicine for Children with Neuroblastoma. J pers med,
Vol.11
(4).
show abstract
full text
Patient-derived preclinical models are now a core component of cancer research and have the ability to drastically improve the predictive power of preclinical therapeutic studies. However, their development and maintenance can be challenging, time consuming, and expensive. For neuroblastoma, a developmental malignancy of the neural crest, it is possible to establish patient-derived models as xenografts in mice and zebrafish, and as spheroids and organoids in vitro. These varied approaches have contributed to comprehensive packages of preclinical evidence in support of new therapeutics for neuroblastoma. We discuss here the ethical and technical considerations for the creation of patient-derived models of neuroblastoma and how their use can be optimized for the study of tumour evolution and preclinical therapies. We also discuss how neuroblastoma patient-derived models might become avatars for personalised medicine for children with this devastating disease..
Georgopoulou, D.
Callari, M.
Rueda, O.M.
Shea, A.
Martin, A.
Giovannetti, A.
Qosaj, F.
Dariush, A.
Chin, S.-.
Carnevalli, L.S.
Provenzano, E.
Greenwood, W.
Lerda, G.
Esmaeilishirazifard, E.
O'Reilly, M.
Serra, V.
Bressan, D.
IMAXT Consortium,
Mills, G.B.
Ali, H.R.
Cosulich, S.S.
Hannon, G.J.
Bruna, A.
Caldas, C.
(2021). Landscapes of cellular phenotypic diversity in breast cancer xenografts and their impact on drug response. Nat commun,
Vol.12
(1),
p. 1998.
show abstract
full text
The heterogeneity of breast cancer plays a major role in drug response and resistance and has been extensively characterized at the genomic level. Here, a single-cell breast cancer mass cytometry (BCMC) panel is optimized to identify cell phenotypes and their oncogenic signalling states in a biobank of patient-derived tumour xenograft (PDTX) models representing the diversity of human breast cancer. The BCMC panel identifies 13 cellular phenotypes (11 human and 2 murine), associated with both breast cancer subtypes and specific genomic features. Pre-treatment cellular phenotypic composition is a determinant of response to anticancer therapies. Single-cell profiling also reveals drug-induced cellular phenotypic dynamics, unravelling previously unnoticed intra-tumour response diversity. The comprehensive view of the landscapes of cellular phenotypic heterogeneity in PDTXs uncovered by the BCMC panel, which is mirrored in primary human tumours, has profound implications for understanding and predicting therapy response and resistance..
Nagarajan, S.
Rao, S.V.
Sutton, J.
Cheeseman, D.
Dunn, S.
Papachristou, E.K.
Prada, J.-.
Couturier, D.-.
Kumar, S.
Kishore, K.
Chilamakuri, C.S.
Glont, S.-.
Archer Goode, E.
Brodie, C.
Guppy, N.
Natrajan, R.
Bruna, A.
Caldas, C.
Russell, A.
Siersbæk, R.
Yusa, K.
Chernukhin, I.
Carroll, J.S.
(2020). ARID1A influences HDAC1/BRD4 activity, intrinsic proliferative capacity and breast cancer treatment response. Nat genet,
Vol.52
(2),
pp. 187-197.
show abstract
full text
Using genome-wide clustered regularly interspaced short palindromic repeats (CRISPR) screens to understand endocrine drug resistance, we discovered ARID1A and other SWI/SNF complex components as the factors most critically required for response to two classes of estrogen receptor-alpha (ER) antagonists. In this context, SWI/SNF-specific gene deletion resulted in drug resistance. Unexpectedly, ARID1A was also the top candidate in regard to response to the bromodomain and extraterminal domain inhibitor JQ1, but in the opposite direction, with loss of ARID1A sensitizing breast cancer cells to bromodomain and extraterminal domain inhibition. We show that ARID1A is a repressor that binds chromatin at ER cis-regulatory elements. However, ARID1A elicits repressive activity in an enhancer-specific, but forkhead box A1-dependent and active, ER-independent manner. Deletion of ARID1A resulted in loss of histone deacetylase 1 binding, increased histone 4 lysine acetylation and subsequent BRD4-driven transcription and growth. ARID1A mutations are more frequent in treatment-resistant disease, and our findings provide mechanistic insight into this process while revealing rational treatment strategies for these patients..
Ros, S.
Wright, A.J.
D'Santos, P.
Hu, D.-.
Hesketh, R.L.
Lubling, Y.
Georgopoulou, D.
Lerda, G.
Couturier, D.-.
Razavi, P.
Pelossof, R.
Batra, A.S.
Mannion, E.
Lewis, D.Y.
Martin, A.
Baird, R.D.
Oliveira, M.
de Boo, L.W.
Linn, S.C.
Scaltriti, M.
Rueda, O.M.
Bruna, A.
Caldas, C.
Brindle, K.M.
(2020). Metabolic Imaging Detects Resistance to PI3Kα Inhibition Mediated by Persistent FOXM1 Expression in ER+ Breast Cancer. Cancer cell,
Vol.38
(4),
pp. 516-533.e9.
show abstract
PIK3CA, encoding the PI3Kα isoform, is the most frequently mutated oncogene in estrogen receptor (ER)-positive breast cancer. Isoform-selective PI3K inhibitors are used clinically but intrinsic and acquired resistance limits their utility. Improved selection of patients that will benefit from these drugs requires predictive biomarkers. We show here that persistent FOXM1 expression following drug treatment is a biomarker of resistance to PI3Kα inhibition in ER+ breast cancer. FOXM1 drives expression of lactate dehydrogenase (LDH) but not hexokinase 2 (HK-II). The downstream metabolic changes can therefore be detected using MRI of LDH-catalyzed hyperpolarized 13C label exchange between pyruvate and lactate but not by positron emission tomography measurements of HK-II-mediated trapping of the glucose analog 2-deoxy-2-[18F]fluorodeoxyglucose. Rapid assessment of treatment response in breast cancer using this imaging method could help identify patients that benefit from PI3Kα inhibition and design drug combinations to counteract the emergence of resistance..
Gris-Oliver, A.
Palafox, M.
Monserrat, L.
Brasó-Maristany, F.
Òdena, A.
Sánchez-Guixé, M.
Ibrahim, Y.H.
Villacampa, G.
Grueso, J.
Parés, M.
Guzmán, M.
Rodríguez, O.
Bruna, A.
Hirst, C.S.
Barnicle, A.
de Bruin, E.C.
Reddy, A.
Schiavon, G.
Arribas, J.
Mills, G.B.
Caldas, C.
Dienstmann, R.
Prat, A.
Nuciforo, P.
Razavi, P.
Scaltriti, M.
Turner, N.C.
Saura, C.
Davies, B.R.
Oliveira, M.
Serra, V.
(2020). Genetic Alterations in the PI3K/AKT Pathway and Baseline AKT Activity Define AKT Inhibitor Sensitivity in Breast Cancer Patient-derived Xenografts. Clin cancer res,
Vol.26
(14),
pp. 3720-3731.
show abstract
PURPOSE: AZD5363/capivasertib is a pan-AKT catalytic inhibitor with promising activity in combination with paclitaxel in triple-negative metastatic breast cancer harboring PI3K/AKT-pathway alterations and in estrogen receptor-positive breast cancer in combination with fulvestrant. Here, we aimed to identify response biomarkers and uncover mechanisms of resistance to AZD5363 and its combination with paclitaxel. EXPERIMENTAL DESIGN: Genetic and proteomic markers were analyzed in 28 HER2-negative patient-derived xenografts (PDXs) and in patient samples, and correlated to AZD5363 sensitivity as single agent and in combination with paclitaxel. RESULTS: Four PDX were derived from patients receiving AZD5363 in the clinic which exhibited concordant treatment response. Mutations in PIK3CA/AKT1 and absence of mTOR complex 1 (mTORC1)-activating alterations, for example, in MTOR or TSC1, were associated with sensitivity to AZD5363 monotherapy. Interestingly, excluding PTEN from the composite biomarker increased its accuracy from 64% to 89%. Moreover, resistant PDXs exhibited low baseline pAKT S473 and residual pS6 S235 upon treatment, suggesting that parallel pathways bypass AKT/S6K1 signaling in these models. We identified two mechanisms of acquired resistance to AZD5363: cyclin D1 overexpression and loss of AKT1 p.E17K. CONCLUSIONS: This study provides insight into putative predictive biomarkers of response and acquired resistance to AZD5363 in HER2-negative metastatic breast cancer..
Rueda, O.M.
Sammut, S.-.
Seoane, J.A.
Chin, S.-.
Caswell-Jin, J.L.
Callari, M.
Batra, R.
Pereira, B.
Bruna, A.
Ali, H.R.
Provenzano, E.
Liu, B.
Parisien, M.
Gillett, C.
McKinney, S.
Green, A.R.
Murphy, L.
Purushotham, A.
Ellis, I.O.
Pharoah, P.D.
Rueda, C.
Aparicio, S.
Caldas, C.
Curtis, C.
(2019). Dynamics of breast-cancer relapse reveal late-recurring ER-positive genomic subgroups. Nature,
Vol.567
(7748),
pp. 399-404.
show abstract
full text
The rates and routes of lethal systemic spread in breast cancer are poorly understood owing to a lack of molecularly characterized patient cohorts with long-term, detailed follow-up data. Long-term follow-up is especially important for those with oestrogen-receptor (ER)-positive breast cancers, which can recur up to two decades after initial diagnosis1-6. It is therefore essential to identify patients who have a high risk of late relapse7-9. Here we present a statistical framework that models distinct disease stages (locoregional recurrence, distant recurrence, breast-cancer-related death and death from other causes) and competing risks of mortality from breast cancer, while yielding individual risk-of-recurrence predictions. We apply this model to 3,240 patients with breast cancer, including 1,980 for whom molecular data are available, and delineate spatiotemporal patterns of relapse across different categories of molecular information (namely immunohistochemical subtypes; PAM50 subtypes, which are based on gene-expression patterns10,11; and integrative or IntClust subtypes, which are based on patterns of genomic copy-number alterations and gene expression12,13). We identify four late-recurring integrative subtypes, comprising about one quarter (26%) of tumours that are both positive for ER and negative for human epidermal growth factor receptor 2, each with characteristic tumour-driving alterations in genomic copy number and a high risk of recurrence (mean 47-62%) up to 20 years after diagnosis. We also define a subgroup of triple-negative breast cancers in which cancer rarely recurs after five years, and a separate subgroup in which patients remain at risk. Use of the integrative subtypes improves the prediction of late, distant relapse beyond what is possible with clinical covariates (nodal status, tumour size, tumour grade and immunohistochemical subtype). These findings highlight opportunities for improved patient stratification and biomarker-driven clinical trials..
Tacconi, E.M.
Badie, S.
De Gregoriis, G.
Reisländer, T.
Lai, X.
Porru, M.
Folio, C.
Moore, J.
Kopp, A.
Baguña Torres, J.
Sneddon, D.
Green, M.
Dedic, S.
Lee, J.W.
Batra, A.S.
Rueda, O.M.
Bruna, A.
Leonetti, C.
Caldas, C.
Cornelissen, B.
Brino, L.
Ryan, A.
Biroccio, A.
Tarsounas, M.
(2019). Chlorambucil targets BRCA1/2-deficient tumours and counteracts PARP inhibitor resistance. Embo mol med,
Vol.11
(7),
p. e9982.
show abstract
full text
Due to compromised homologous recombination (HR) repair, BRCA1- and BRCA2-mutated tumours accumulate DNA damage and genomic rearrangements conducive of tumour progression. To identify drugs that target specifically BRCA2-deficient cells, we screened a chemical library containing compounds in clinical use. The top hit was chlorambucil, a bifunctional alkylating agent used for the treatment of chronic lymphocytic leukaemia (CLL). We establish that chlorambucil is specifically toxic to BRCA1/2-deficient cells, including olaparib-resistant and cisplatin-resistant ones, suggesting the potential clinical use of chlorambucil against disease which has become resistant to these drugs. Additionally, chlorambucil eradicates BRCA2-deficient xenografts and inhibits growth of olaparib-resistant patient-derived tumour xenografts (PDTXs). We demonstrate that chlorambucil inflicts replication-associated DNA double-strand breaks (DSBs), similarly to cisplatin, and we identify ATR, FANCD2 and the SNM1A nuclease as determinants of sensitivity to both drugs. Importantly, chlorambucil is substantially less toxic to normal cells and tissues in vitro and in vivo relative to cisplatin. Because chlorambucil and cisplatin are equally effective inhibitors of BRCA2-compromised tumours, our results indicate that chlorambucil has a higher therapeutic index than cisplatin in targeting BRCA-deficient tumours..
Gómez-Miragaya, J.
Díaz-Navarro, A.
Tonda, R.
Beltran, S.
Palomero, L.
Palafox, M.
Dobrolecki, L.E.
Huang, C.
Vasaikar, S.
Zhang, B.
Wulf, G.M.
Collado-Sole, A.
Trinidad, E.M.
Muñoz, P.
Paré, L.
Prat, A.
Bruna, A.
Caldas, C.
Arribas, J.
Soler-Monso, M.T.
Petit, A.
Balmaña, J.
Cruz, C.
Serra, V.
Pujana, M.A.
Lewis, M.T.
Puente, X.S.
González-Suárez, E.
(2019). Chromosome 12p Amplification in Triple-Negative/BRCA1-Mutated Breast Cancer Associates with Emergence of Docetaxel Resistance and Carboplatin Sensitivity. Cancer res,
Vol.79
(16),
pp. 4258-4270.
show abstract
Taxanes are the mainstay of treatment in triple-negative breast cancer (TNBC), with de novo and acquired resistance limiting patient's survival. To investigate the genetic basis of docetaxel resistance in TNBC, exome sequencing was performed on matched TNBC patient-derived xenografts (PDX) sensitive to docetaxel and their counterparts that developed resistance in vivo upon continuous drug exposure. Most mutations, small insertions/deletions, and copy number alterations detected in the initial TNBC human metastatic samples were maintained after serial passages in mice and emergence of resistance. We identified a chromosomal amplification of chr12p in a human BRCA1-mutated metastatic sample and the derived chemoresistant PDX, but not in the matched docetaxel-sensitive PDX tumor. Chr12p amplification was validated in a second pair of docetaxel-sensitive/resistant BRCA1-mutated PDXs and after short-term docetaxel treatment in several TNBC/BRCA1-mutated PDXs and cell lines, as well as during metastatic recurrence in a patient with BRCA1-mutated breast cancer who had progressed on docetaxel treatment. Analysis of clinical data indicates an association between chr12p amplification and patients with TNBC/basal-like breast cancer, a BRCA1 mutational signature, and poor survival after chemotherapy. Detection of chr12p amplification in a cohort of TNBC PDX models was associated with an improved response to carboplatin. Our findings reveal tumor clonal dynamics during chemotherapy treatments and suggest that a preexisting population harboring chr12p amplification is associated with the emergence of docetaxel resistance and carboplatin responsiveness in TNBC/BRCA1-mutated tumors. SIGNIFICANCE: Chr12p copy number gains indicate rapid emergence of resistance to docetaxel and increased sensitivity to carboplatin, therefore sequential docetaxel/carboplatin treatment could improve survival in TNBC/BRCA1 patients. GRAPHICAL ABSTRACT: http://cancerres.aacrjournals.org/content/canres/79/16/4258/F1.large.jpg..
Avanzato, D.
Pupo, E.
Ducano, N.
Isella, C.
Bertalot, G.
Luise, C.
Pece, S.
Bruna, A.
Rueda, O.M.
Caldas, C.
Di Fiore, P.P.
Sapino, A.
Lanzetti, L.
(2018). High USP6NL Levels in Breast Cancer Sustain Chronic AKT Phosphorylation and GLUT1 Stability Fueling Aerobic Glycolysis. Cancer res,
Vol.78
(13),
pp. 3432-3444.
show abstract
USP6NL, also named RN-tre, is a GTPase-activating protein involved in control of endocytosis and signal transduction. Here we report that USP6NL is overexpressed in breast cancer, mainly of the basal-like/integrative cluster 10 subtype. Increased USP6NL levels were accompanied by gene amplification and were associated with worse prognosis in the METABRIC dataset, retaining prognostic value in multivariable analysis. High levels of USP6NL in breast cancer cells delayed endocytosis and degradation of the EGFR, causing chronic AKT (protein kinase B) activation. In turn, AKT stabilized the glucose transporter GLUT1 at the plasma membrane, increasing aerobic glycolysis. In agreement, elevated USP6NL sensitized breast cancer cells to glucose deprivation, indicating that their glycolytic capacity relies on this protein. Depletion of USP6NL accelerated EGFR/AKT downregulation and GLUT1 degradation, impairing cell proliferation exclusively in breast cancer cells that harbored increased levels of USP6NL. Overall, these findings argue that USP6NL overexpression generates a metabolic rewiring that is essential to foster the glycolytic demand of breast cancer cells and promote their proliferation.Significance: USP6NL overexpression leads to glycolysis addiction of breast cancer cells and presents a point of metabolic vulnerability for therapeutic targeting in a subset of aggressive basal-like breast tumors.Graphical Abstract: http://cancerres.aacrjournals.org/content/canres/78/13/3432/F1.large.jpg Cancer Res; 78(13); 3432-44. ©2018 AACR..
Cruz, C.
Castroviejo-Bermejo, M.
Gutiérrez-Enríquez, S.
Llop-Guevara, A.
Ibrahim, Y.H.
Gris-Oliver, A.
Bonache, S.
Morancho, B.
Bruna, A.
Rueda, O.M.
Lai, Z.
Polanska, U.M.
Jones, G.N.
Kristel, P.
de Bustos, L.
Guzman, M.
Rodríguez, O.
Grueso, J.
Montalban, G.
Caratú, G.
Mancuso, F.
Fasani, R.
Jiménez, J.
Howat, W.J.
Dougherty, B.
Vivancos, A.
Nuciforo, P.
Serres-Créixams, X.
Rubio, I.T.
Oaknin, A.
Cadogan, E.
Barrett, J.C.
Caldas, C.
Baselga, J.
Saura, C.
Cortés, J.
Arribas, J.
Jonkers, J.
Díez, O.
O'Connor, M.J.
Balmaña, J.
Serra, V.
(2018). RAD51 foci as a functional biomarker of homologous recombination repair and PARP inhibitor resistance in germline BRCA-mutated breast cancer. Ann oncol,
Vol.29
(5),
pp. 1203-1210.
show abstract
BACKGROUND: BRCA1 and BRCA2 (BRCA1/2)-deficient tumors display impaired homologous recombination repair (HRR) and enhanced sensitivity to DNA damaging agents or to poly(ADP-ribose) polymerase (PARP) inhibitors (PARPi). Their efficacy in germline BRCA1/2 (gBRCA1/2)-mutated metastatic breast cancers has been recently confirmed in clinical trials. Numerous mechanisms of PARPi resistance have been described, whose clinical relevance in gBRCA-mutated breast cancer is unknown. This highlights the need to identify functional biomarkers to better predict PARPi sensitivity. PATIENTS AND METHODS: We investigated the in vivo mechanisms of PARPi resistance in gBRCA1 patient-derived tumor xenografts (PDXs) exhibiting differential response to PARPi. Analysis included exome sequencing and immunostaining of DNA damage response proteins to functionally evaluate HRR. Findings were validated in a retrospective sample set from gBRCA1/2-cancer patients treated with PARPi. RESULTS: RAD51 nuclear foci, a surrogate marker of HRR functionality, were the only common feature in PDX and patient samples with primary or acquired PARPi resistance. Consistently, low RAD51 was associated with objective response to PARPi. Evaluation of the RAD51 biomarker in untreated tumors was feasible due to endogenous DNA damage. In PARPi-resistant gBRCA1 PDXs, genetic analysis found no in-frame secondary mutations, but BRCA1 hypomorphic proteins in 60% of the models, TP53BP1-loss in 20% and RAD51-amplification in one sample, none mutually exclusive. Conversely, one of three PARPi-resistant gBRCA2 tumors displayed BRCA2 restoration by exome sequencing. In PDXs, PARPi resistance could be reverted upon combination of a PARPi with an ataxia-telangiectasia mutated (ATM) inhibitor. CONCLUSION: Detection of RAD51 foci in gBRCA tumors correlates with PARPi resistance regardless of the underlying mechanism restoring HRR function. This is a promising biomarker to be used in the clinic to better select patients for PARPi therapy. Our study also supports the clinical development of PARPi combinations such as those with ATM inhibitors..
Vervoort, S.J.
de Jong, O.G.
Roukens, M.G.
Frederiks, C.L.
Vermeulen, J.F.
Lourenço, A.R.
Bella, L.
Vidakovic, A.T.
Sandoval, J.L.
Moelans, C.
van Amersfoort, M.
Dallman, M.J.
Bruna, A.
Caldas, C.
Nieuwenhuis, E.
van der Wall, E.
Derksen, P.
van Diest, P.
Verhaar, M.C.
Lam, E.W.
Mokry, M.
Coffer, P.J.
(2018). Global transcriptional analysis identifies a novel role for SOX4 in tumor-induced angiogenesis. Elife,
Vol.7.
show abstract
full text
The expression of the transcription factor SOX4 is increased in many human cancers, however, the pro-oncogenic capacity of SOX4 can vary greatly depending on the type of tumor. Both the contextual nature and the mechanisms underlying the pro-oncogenic SOX4 response remain unexplored. Here, we demonstrate that in mammary tumorigenesis, the SOX4 transcriptional network is dictated by the epigenome and is enriched for pro-angiogenic processes. We show that SOX4 directly regulates endothelin-1 (ET-1) expression and can thereby promote tumor-induced angiogenesis both in vitro and in vivo. Furthermore, in breast tumors, SOX4 expression correlates with blood vessel density and size, and predicts poor-prognosis in patients with breast cancer. Our data provide novel mechanistic insights into context-dependent SOX4 target gene selection, and uncover a novel pro-oncogenic role for this transcription factor in promoting tumor-induced angiogenesis. These findings establish a key role for SOX4 in promoting metastasis through exploiting diverse pro-tumorigenic pathways..
Callari, M.
Batra, A.S.
Batra, R.N.
Sammut, S.-.
Greenwood, W.
Clifford, H.
Hercus, C.
Chin, S.-.
Bruna, A.
Rueda, O.M.
Caldas, C.
(2018). Computational approach to discriminate human and mouse sequences in patient-derived tumour xenografts. Bmc genomics,
Vol.19
(1),
p. 19.
show abstract
BACKGROUND: Patient-Derived Tumour Xenografts (PDTXs) have emerged as the pre-clinical models that best represent clinical tumour diversity and intra-tumour heterogeneity. The molecular characterization of PDTXs using High-Throughput Sequencing (HTS) is essential; however, the presence of mouse stroma is challenging for HTS data analysis. Indeed, the high homology between the two genomes results in a proportion of mouse reads being mapped as human. RESULTS: In this study we generated Whole Exome Sequencing (WES), Reduced Representation Bisulfite Sequencing (RRBS) and RNA sequencing (RNA-seq) data from samples with known mixtures of mouse and human DNA or RNA and from a cohort of human breast cancers and their derived PDTXs. We show that using an In silico Combined human-mouse Reference Genome (ICRG) for alignment discriminates between human and mouse reads with up to 99.9% accuracy and decreases the number of false positive somatic mutations caused by misalignment by >99.9%. We also derived a model to estimate the human DNA content in independent PDTX samples. For RNA-seq and RRBS data analysis, the use of the ICRG allows dissecting computationally the transcriptome and methylome of human tumour cells and mouse stroma. In a direct comparison with previously reported approaches, our method showed similar or higher accuracy while requiring significantly less computing time. CONCLUSIONS: The computational pipeline we describe here is a valuable tool for the molecular analysis of PDTXs as well as any other mixture of DNA or RNA species..
Xue, Z.
Vis, D.J.
Bruna, A.
Sustic, T.
van Wageningen, S.
Batra, A.S.
Rueda, O.M.
Bosdriesz, E.
Caldas, C.
Wessels, L.F.
Bernards, R.
(2018). MAP3K1 and MAP2K4 mutations are associated with sensitivity to MEK inhibitors in multiple cancer models. Cell res,
Vol.28
(7),
pp. 719-729.
show abstract
Activation of the mitogen-activated protein kinase (MAPK) pathway is frequent in cancer. Drug development efforts have been focused on kinases in this pathway, most notably on RAF and MEK. We show here that MEK inhibition activates JNK-JUN signaling through suppression of DUSP4, leading to activation of HER Receptor Tyrosine Kinases. This stimulates the MAPK pathway in the presence of drug, thereby blunting the effect of MEK inhibition. Cancers that have lost MAP3K1 or MAP2K4 fail to activate JNK-JUN. Consequently, loss-of-function mutations in either MAP3K1 or MAP2K4 confer sensitivity to MEK inhibition by disabling JNK-JUN-mediated feedback loop upon MEK inhibition. In a panel of 168 Patient Derived Xenograft (PDX) tumors, MAP3K1 and MAP2K4 mutation status is a strong predictor of response to MEK inhibition. Our findings suggest that cancers having mutations in MAP3K1 or MAP2K4, which are frequent in tumors of breast, prostate and colon, may respond to MEK inhibitors. Our findings also suggest that MAP3K1 and MAP2K4 are potential drug targets in combination with MEK inhibitors, in spite of the fact that they are encoded by tumor suppressor genes..
Dev, H.
Chiang, T.-.
Lescale, C.
de Krijger, I.
Martin, A.G.
Pilger, D.
Coates, J.
Sczaniecka-Clift, M.
Wei, W.
Ostermaier, M.
Herzog, M.
Lam, J.
Shea, A.
Demir, M.
Wu, Q.
Yang, F.
Fu, B.
Lai, Z.
Balmus, G.
Belotserkovskaya, R.
Serra, V.
O'Connor, M.J.
Bruna, A.
Beli, P.
Pellegrini, L.
Caldas, C.
Deriano, L.
Jacobs, J.J.
Galanty, Y.
Jackson, S.P.
(2018). Shieldin complex promotes DNA end-joining and counters homologous recombination in BRCA1-null cells. Nat cell biol,
Vol.20
(8),
pp. 954-965.
show abstract
full text
BRCA1 deficiencies cause breast, ovarian, prostate and other cancers, and render tumours hypersensitive to poly(ADP-ribose) polymerase (PARP) inhibitors. To understand the resistance mechanisms, we conducted whole-genome CRISPR-Cas9 synthetic-viability/resistance screens in BRCA1-deficient breast cancer cells treated with PARP inhibitors. We identified two previously uncharacterized proteins, C20orf196 and FAM35A, whose inactivation confers strong PARP-inhibitor resistance. Mechanistically, we show that C20orf196 and FAM35A form a complex, 'Shieldin' (SHLD1/2), with FAM35A interacting with single-stranded DNA through its C-terminal oligonucleotide/oligosaccharide-binding fold region. We establish that Shieldin acts as the downstream effector of 53BP1/RIF1/MAD2L2 to promote DNA double-strand break (DSB) end-joining by restricting DSB resection and to counteract homologous recombination by antagonizing BRCA2/RAD51 loading in BRCA1-deficient cells. Notably, Shieldin inactivation further sensitizes BRCA1-deficient cells to cisplatin, suggesting how defining the SHLD1/2 status of BRCA1-deficient tumours might aid patient stratification and yield new treatment opportunities. Highlighting this potential, we document reduced SHLD1/2 expression in human breast cancers displaying intrinsic or acquired PARP-inhibitor resistance..
Castroviejo-Bermejo, M.
Cruz, C.
Llop-Guevara, A.
Gutiérrez-Enríquez, S.
Ducy, M.
Ibrahim, Y.H.
Gris-Oliver, A.
Pellegrino, B.
Bruna, A.
Guzmán, M.
Rodríguez, O.
Grueso, J.
Bonache, S.
Moles-Fernández, A.
Villacampa, G.
Viaplana, C.
Gómez, P.
Vidal, M.
Peg, V.
Serres-Créixams, X.
Dellaire, G.
Simard, J.
Nuciforo, P.
Rubio, I.T.
Dienstmann, R.
Barrett, J.C.
Caldas, C.
Baselga, J.
Saura, C.
Cortés, J.
Déas, O.
Jonkers, J.
Masson, J.-.
Cairo, S.
Judde, J.-.
O'Connor, M.J.
Díez, O.
Balmaña, J.
Serra, V.
(2018). A RAD51 assay feasible in routine tumor samples calls PARP inhibitor response beyond BRCA mutation. Embo mol med,
Vol.10
(12).
show abstract
full text
Poly(ADP-ribose) polymerase (PARP) inhibitors (PARPi) are effective in cancers with defective homologous recombination DNA repair (HRR), including BRCA1/2-related cancers. A test to identify additional HRR-deficient tumors will help to extend their use in new indications. We evaluated the activity of the PARPi olaparib in patient-derived tumor xenografts (PDXs) from breast cancer (BC) patients and investigated mechanisms of sensitivity through exome sequencing, BRCA1 promoter methylation analysis, and immunostaining of HRR proteins, including RAD51 nuclear foci. In an independent BC PDX panel, the predictive capacity of the RAD51 score and the homologous recombination deficiency (HRD) score were compared. To examine the clinical feasibility of the RAD51 assay, we scored archival breast tumor samples, including PALB2-related hereditary cancers. The RAD51 score was highly discriminative of PARPi sensitivity versus PARPi resistance in BC PDXs and outperformed the genomic test. In clinical samples, all PALB2-related tumors were classified as HRR-deficient by the RAD51 score. The functional biomarker RAD51 enables the identification of PARPi-sensitive BC and broadens the population who may benefit from this therapy beyond BRCA1/2-related cancers..
Vervoort, S.J.
Lourenço, A.R.
Tufegdzic Vidakovic, A.
Mocholi, E.
Sandoval, J.L.
Rueda, O.M.
Frederiks, C.
Pals, C.
Peeters, J.G.
Caldas, C.
Bruna, A.
Coffer, P.J.
(2018). SOX4 can redirect TGF-β-mediated SMAD3-transcriptional output in a context-dependent manner to promote tumorigenesis. Nucleic acids res,
Vol.46
(18),
pp. 9578-9590.
show abstract
Expression of the transcription factor SOX4 is often elevated in human cancers, where it generally correlates with tumor-progression and poor-disease outcome. Reduction of SOX4 expression results in both diminished tumor-incidence and metastasis. In breast cancer, TGF-β-mediated induction of SOX4 has been shown to contribute to epithelial-to-mesenchymal transition (EMT), which controls pro-metastatic events. Here, we identify SMAD3 as a novel, functionally relevant SOX4 interaction partner. Genome-wide analysis showed that SOX4 and SMAD3 co-occupy a large number of genomic loci in a cell-type specific manner. Moreover, SOX4 expression was required for TGF-β-mediated induction of a subset of SMAD3/SOX4-co-bound genes regulating migration and extracellular matrix-associated processes, and correlating with poor-prognosis. These findings identify SOX4 as an important SMAD3 co-factor controlling transcription of pro-metastatic genes and context-dependent shaping of the cellular response to TGF-β. Targeted disruption of the interaction between these factors may have the potential to disrupt pro-oncogenic TGF-β signaling, thereby impairing tumorigenesis..
Pensa, S.
Lazarus, K.A.
Bach, K.
Santolla, M.F.
Maggiolini, M.
Cassidy, J.
Batra, A.S.
Bruna, A.
Mohammed, H.
Liu, P.
Carroll, J.S.
Caldas, C.
Marioni, J.C.
Khaled, W.T.
(2018). Bcl11a Marks Mammary Progenitor Cells and Promotes Early Cellular Changes Associated with TNBC by Recruiting Chd8. ,
.
Meehan, T.F.
Conte, N.
Goldstein, T.
Inghirami, G.
Murakami, M.A.
Brabetz, S.
Gu, Z.
Wiser, J.A.
Dunn, P.
Begley, D.A.
Krupke, D.M.
Bertotti, A.
Bruna, A.
Brush, M.H.
Byrne, A.T.
Caldas, C.
Christie, A.L.
Clark, D.A.
Dowst, H.
Dry, J.R.
Doroshow, J.H.
Duchamp, O.
Evrard, Y.A.
Ferretti, S.
Frese, K.K.
Goodwin, N.C.
Greenawalt, D.
Haendel, M.A.
Hermans, E.
Houghton, P.J.
Jonkers, J.
Kemper, K.
Khor, T.O.
Lewis, M.T.
Lloyd, K.C.
Mason, J.
Medico, E.
Neuhauser, S.B.
Olson, J.M.
Peeper, D.S.
Rueda, O.M.
Seong, J.K.
Trusolino, L.
Vinolo, E.
Wechsler-Reya, R.J.
Weinstock, D.M.
Welm, A.
Weroha, S.J.
Amant, F.
Pfister, S.M.
Kool, M.
Parkinson, H.
Butte, A.J.
Bult, C.J.
(2017). PDX-MI: Minimal Information for Patient-Derived Tumor Xenograft Models. Cancer res,
Vol.77
(21),
pp. e62-e66.
show abstract
Patient-derived tumor xenograft (PDX) mouse models have emerged as an important oncology research platform to study tumor evolution, mechanisms of drug response and resistance, and tailoring chemotherapeutic approaches for individual patients. The lack of robust standards for reporting on PDX models has hampered the ability of researchers to find relevant PDX models and associated data. Here we present the PDX models minimal information standard (PDX-MI) for reporting on the generation, quality assurance, and use of PDX models. PDX-MI defines the minimal information for describing the clinical attributes of a patient's tumor, the processes of implantation and passaging of tumors in a host mouse strain, quality assurance methods, and the use of PDX models in cancer research. Adherence to PDX-MI standards will facilitate accurate search results for oncology models and their associated data across distributed repository databases and promote reproducibility in research studies using these models. Cancer Res; 77(21); e62-66. ©2017 AACR..
Byrne, A.T.
Alférez, D.G.
Amant, F.
Annibali, D.
Arribas, J.
Biankin, A.V.
Bruna, A.
Budinská, E.
Caldas, C.
Chang, D.K.
Clarke, R.B.
Clevers, H.
Coukos, G.
Dangles-Marie, V.
Eckhardt, S.G.
Gonzalez-Suarez, E.
Hermans, E.
Hidalgo, M.
Jarzabek, M.A.
de Jong, S.
Jonkers, J.
Kemper, K.
Lanfrancone, L.
Mælandsmo, G.M.
Marangoni, E.
Marine, J.-.
Medico, E.
Norum, J.H.
Palmer, H.G.
Peeper, D.S.
Pelicci, P.G.
Piris-Gimenez, A.
Roman-Roman, S.
Rueda, O.M.
Seoane, J.
Serra, V.
Soucek, L.
Vanhecke, D.
Villanueva, A.
Vinolo, E.
Bertotti, A.
Trusolino, L.
(2017). Interrogating open issues in cancer precision medicine with patient-derived xenografts. Nat rev cancer,
Vol.17
(4),
pp. 254-268.
show abstract
Patient-derived xenografts (PDXs) have emerged as an important platform to elucidate new treatments and biomarkers in oncology. PDX models are used to address clinically relevant questions, including the contribution of tumour heterogeneity to therapeutic responsiveness, the patterns of cancer evolutionary dynamics during tumour progression and under drug pressure, and the mechanisms of resistance to treatment. The ability of PDX models to predict clinical outcomes is being improved through mouse humanization strategies and the implementation of co-clinical trials, within which patients and PDXs reciprocally inform therapeutic decisions. This Opinion article discusses aspects of PDX modelling that are relevant to these questions and highlights the merits of shared PDX resources to advance cancer medicine from the perspective of EurOPDX, an international initiative devoted to PDX-based research..
Tacconi, E.M.
Lai, X.
Folio, C.
Porru, M.
Zonderland, G.
Badie, S.
Michl, J.
Sechi, I.
Rogier, M.
Matía García, V.
Batra, A.S.
Rueda, O.M.
Bouwman, P.
Jonkers, J.
Ryan, A.
Reina-San-Martin, B.
Hui, J.
Tang, N.
Bruna, A.
Biroccio, A.
Tarsounas, M.
(2017). BRCA1 and BRCA2 tumor suppressors protect against endogenous acetaldehyde toxicity. Embo mol med,
Vol.9
(10),
pp. 1398-1414.
show abstract
full text
Maintenance of genome integrity requires the functional interplay between Fanconi anemia (FA) and homologous recombination (HR) repair pathways. Endogenous acetaldehyde, a product of cellular metabolism, is a potent source of DNA damage, particularly toxic to cells and mice lacking the FA protein FANCD2. Here, we investigate whether HR-compromised cells are sensitive to acetaldehyde, similarly to FANCD2-deficient cells. We demonstrate that inactivation of HR factors BRCA1, BRCA2, or RAD51 hypersensitizes cells to acetaldehyde treatment, in spite of the FA pathway being functional. Aldehyde dehydrogenases (ALDHs) play key roles in endogenous acetaldehyde detoxification, and their chemical inhibition leads to cellular acetaldehyde accumulation. We find that disulfiram (Antabuse), an ALDH2 inhibitor in widespread clinical use for the treatment of alcoholism, selectively eliminates BRCA1/2-deficient cells. Consistently, Aldh2 gene inactivation suppresses proliferation of HR-deficient mouse embryonic fibroblasts (MEFs) and human fibroblasts. Hypersensitivity of cells lacking BRCA2 to acetaldehyde stems from accumulation of toxic replication-associated DNA damage, leading to checkpoint activation, G2/M arrest, and cell death. Acetaldehyde-arrested replication forks require BRCA2 and FANCD2 for protection against MRE11-dependent degradation. Importantly, acetaldehyde specifically inhibits in vivo the growth of BRCA1/2-deficient tumors and ex vivo in patient-derived tumor xenograft cells (PDTCs), including those that are resistant to poly (ADP-ribose) polymerase (PARP) inhibitors. The work presented here therefore identifies acetaldehyde metabolism as a potential therapeutic target for the selective elimination of BRCA1/2-deficient cells and tumors..
Callari, M.
Sammut, S.-.
De Mattos-Arruda, L.
Bruna, A.
Rueda, O.M.
Chin, S.-.
Caldas, C.
(2017). Intersect-then-combine approach: improving the performance of somatic variant calling in whole exome sequencing data using multiple aligners and callers. Genome med,
Vol.9
(1),
p. 35.
show abstract
Bioinformatic analysis of genomic sequencing data to identify somatic mutations in cancer samples is far from achieving the required robustness and standardisation. In this study we generated a whole exome sequencing benchmark dataset using the platinum genome sample NA12878 and developed an intersect-then-combine (ITC) approach to increase the accuracy in calling single nucleotide variants (SNVs) and indels in tumour-normal pairs. We evaluated the effect of alignment, base quality recalibration, mutation caller and filtering on sensitivity and false positive rate. The ITC approach increased the sensitivity up to 17.1%, without increasing the false positive rate per megabase (FPR/Mb) and its validity was confirmed in a set of clinical samples..
Cassidy, J.W.
Batra, A.S.
Greenwood, W.
Bruna, A.
(2016). Patient-derived tumour xenografts for breast cancer drug discovery. Endocr relat cancer,
Vol.23
(12),
pp. T259-T270.
show abstract
full text
Despite remarkable advances in our understanding of the drivers of human malignancies, new targeted therapies often fail to show sufficient efficacy in clinical trials. Indeed, the cost of bringing a new agent to market has risen substantially in the last several decades, in part fuelled by extensive reliance on preclinical models that fail to accurately reflect tumour heterogeneity. To halt unsustainable rates of attrition in the drug discovery process, we must develop a new generation of preclinical models capable of reflecting the heterogeneity of varying degrees of complexity found in human cancers. Patient-derived tumour xenograft (PDTX) models prevail as arguably the most powerful in this regard because they capture cancer's heterogeneous nature. Herein, we review current breast cancer models and their use in the drug discovery process, before discussing best practices for developing a highly annotated cohort of PDTX models. We describe the importance of extensive multidimensional molecular and functional characterisation of models and combination drug-drug screens to identify complex biomarkers of drug resistance and response. We reflect on our own experiences and propose the use of a cost-effective intermediate pharmacogenomic platform (the PDTX-PDTC platform) for breast cancer drug and biomarker discovery. We discuss the limitations and unanswered questions of PDTX models; yet, still strongly envision that their use in basic and translational research will dramatically change our understanding of breast cancer biology and how to more effectively treat it..
Bruna, A.
Rueda, O.M.
Greenwood, W.
Batra, A.S.
Callari, M.
Batra, R.N.
Pogrebniak, K.
Sandoval, J.
Cassidy, J.W.
Tufegdzic-Vidakovic, A.
Sammut, S.-.
Jones, L.
Provenzano, E.
Baird, R.
Eirew, P.
Hadfield, J.
Eldridge, M.
McLaren-Douglas, A.
Barthorpe, A.
Lightfoot, H.
O'Connor, M.J.
Gray, J.
Cortes, J.
Baselga, J.
Marangoni, E.
Welm, A.L.
Aparicio, S.
Serra, V.
Garnett, M.J.
Caldas, C.
(2016). A Biobank of Breast Cancer Explants with Preserved Intra-tumor Heterogeneity to Screen Anticancer Compounds. Cell,
Vol.167
(1),
pp. 260-274.e22.
show abstract
full text
The inter- and intra-tumor heterogeneity of breast cancer needs to be adequately captured in pre-clinical models. We have created a large collection of breast cancer patient-derived tumor xenografts (PDTXs), in which the morphological and molecular characteristics of the originating tumor are preserved through passaging in the mouse. An integrated platform combining in vivo maintenance of these PDTXs along with short-term cultures of PDTX-derived tumor cells (PDTCs) was optimized. Remarkably, the intra-tumor genomic clonal architecture present in the originating breast cancers was mostly preserved upon serial passaging in xenografts and in short-term cultured PDTCs. We assessed drug responses in PDTCs on a high-throughput platform and validated several ex vivo responses in vivo. The biobank represents a powerful resource for pre-clinical breast cancer pharmacogenomic studies (http://caldaslab.cruk.cam.ac.uk/bcape), including identification of biomarkers of response or resistance..
Bruna, A.
Rueda, O.M.
Caldas, C.
(2016). Modeling Breast Cancer Intertumor and Intratumor Heterogeneity Using Xenografts. Cold spring harb symp quant biol,
Vol.81,
pp. 227-230.
show abstract
Breast cancer is a heterogeneous disease that can be stratified in at least 10 different subtypes. We present here a platform for derivation of preclinical models based on patient-derived tumor xenografts (PDTXs) that represent these subgroups. These models preserve the transcriptome, methylome, copy-number, and mutational landscape features of the tumor of origin through different passaging. Furthermore, the intratumoral composition of these models is formed by communities of clones very similar to the ones present in the originating tumor. Finally, we show that short-term cultures of cells from these models (PDTX-derived tumor cells, PDTCs) also preserve the molecular features of the tumor and can be used for high-throughput drug testing of single compounds or combinations, with high reproducibility and clinical predictive power..
Cassidy, J.W.
Caldas, C.
Bruna, A.
(2015). Maintaining Tumor Heterogeneity in Patient-Derived Tumor Xenografts. Cancer res,
Vol.75
(15),
pp. 2963-2968.
show abstract
Preclinical models often fail to capture the diverse heterogeneity of human malignancies and as such lack clinical predictive power. Patient-derived tumor xenografts (PDX) have emerged as a powerful technology: capable of retaining the molecular heterogeneity of their originating sample. However, heterogeneity within a tumor is governed by both cell-autonomous (e.g., genetic and epigenetic heterogeneity) and non-cell-autonomous (e.g., stromal heterogeneity) drivers. Although PDXs can largely recapitulate the polygenomic architecture of human tumors, they do not fully account for heterogeneity in the tumor microenvironment. Hence, these models have substantial utility in basic and translational research in cancer biology; however, study of stromal or immune drivers of malignant progression may be limited. Similarly, PDX models offer the ability to conduct patient-specific in vivo and ex vivo drug screens, but stromal contributions to treatment responses may be under-represented. This review discusses the sources and consequences of intratumor heterogeneity and how these are recapitulated in the PDX model. Limitations of the current generation of PDXs are discussed and strategies to improve several aspects of the model with respect to preserving heterogeneity are proposed..
Mohammed, H.
Russell, I.A.
Stark, R.
Rueda, O.M.
Hickey, T.E.
Tarulli, G.A.
Serandour, A.A.
Birrell, S.N.
Bruna, A.
Saadi, A.
Menon, S.
Hadfield, J.
Pugh, M.
Raj, G.V.
Brown, G.D.
D'Santos, C.
Robinson, J.L.
Silva, G.
Launchbury, R.
Perou, C.M.
Stingl, J.
Caldas, C.
Tilley, W.D.
Carroll, J.S.
(2015). Progesterone receptor modulates ERα action in breast cancer. Nature,
Vol.523
(7560),
pp. 313-317.
show abstract
full text
Progesterone receptor (PR) expression is used as a biomarker of oestrogen receptor-α (ERα) function and breast cancer prognosis. Here we show that PR is not merely an ERα-induced gene target, but is also an ERα-associated protein that modulates its behaviour. In the presence of agonist ligands, PR associates with ERα to direct ERα chromatin binding events within breast cancer cells, resulting in a unique gene expression programme that is associated with good clinical outcome. Progesterone inhibited oestrogen-mediated growth of ERα(+) cell line xenografts and primary ERα(+) breast tumour explants, and had increased anti-proliferative effects when coupled with an ERα antagonist. Copy number loss of PGR, the gene coding for PR, is a common feature in ERα(+) breast cancers, explaining lower PR levels in a subset of cases. Our findings indicate that PR functions as a molecular rheostat to control ERα chromatin binding and transcriptional activity, which has important implications for prognosis and therapeutic interventions..
Eirew, P.
Steif, A.
Khattra, J.
Ha, G.
Yap, D.
Farahani, H.
Gelmon, K.
Chia, S.
Mar, C.
Wan, A.
Laks, E.
Biele, J.
Shumansky, K.
Rosner, J.
McPherson, A.
Nielsen, C.
Roth, A.J.
Lefebvre, C.
Bashashati, A.
de Souza, C.
Siu, C.
Aniba, R.
Brimhall, J.
Oloumi, A.
Osako, T.
Bruna, A.
Sandoval, J.L.
Algara, T.
Greenwood, W.
Leung, K.
Cheng, H.
Xue, H.
Wang, Y.
Lin, D.
Mungall, A.J.
Moore, R.
Zhao, Y.
Lorette, J.
Nguyen, L.
Huntsman, D.
Eaves, C.J.
Hansen, C.
Marra, M.A.
Caldas, C.
Shah, S.P.
Aparicio, S.
(2015). Dynamics of genomic clones in breast cancer patient xenografts at single-cell resolution. Nature,
Vol.518
(7539),
pp. 422-426.
show abstract
full text
Human cancers, including breast cancers, comprise clones differing in mutation content. Clones evolve dynamically in space and time following principles of Darwinian evolution, underpinning important emergent features such as drug resistance and metastasis. Human breast cancer xenoengraftment is used as a means of capturing and studying tumour biology, and breast tumour xenografts are generally assumed to be reasonable models of the originating tumours. However, the consequences and reproducibility of engraftment and propagation on the genomic clonal architecture of tumours have not been systematically examined at single-cell resolution. Here we show, using deep-genome and single-cell sequencing methods, the clonal dynamics of initial engraftment and subsequent serial propagation of primary and metastatic human breast cancers in immunodeficient mice. In all 15 cases examined, clonal selection on engraftment was observed in both primary and metastatic breast tumours, varying in degree from extreme selective engraftment of minor (<5% of starting population) clones to moderate, polyclonal engraftment. Furthermore, ongoing clonal dynamics during serial passaging is a feature of tumours experiencing modest initial selection. Through single-cell sequencing, we show that major mutation clusters estimated from tumour population sequencing relate predictably to the most abundant clonal genotypes, even in clonally complex and rapidly evolving cases. Finally, we show that similar clonal expansion patterns can emerge in independent grafts of the same starting tumour population, indicating that genomic aberrations can be reproducible determinants of evolutionary trajectories. Our results show that measurement of genomically defined clonal population dynamics will be highly informative for functional studies using patient-derived breast cancer xenoengraftment..
Tufegdzic Vidakovic, A.
Rueda, O.M.
Vervoort, S.J.
Sati Batra, A.
Goldgraben, M.A.
Uribe-Lewis, S.
Greenwood, W.
Coffer, P.J.
Bruna, A.
Caldas, C.
(2015). Context-Specific Effects of TGF-β/SMAD3 in Cancer Are Modulated by the Epigenome. Cell rep,
Vol.13
(11),
pp. 2480-2490.
show abstract
The transforming growth factor beta (TGF-β) signaling pathway exerts opposing effects on cancer cells, acting as either a tumor promoter or a tumor suppressor. Here, we show that these opposing effects are a result of the synergy between SMAD3, a downstream effector of TGF-β signaling, and the distinct epigenomes of breast-tumor-initiating cells (BTICs). These effects of TGF-β are associated with distinct gene expression programs, but genomic SMAD3 binding patterns are highly similar in the BTIC-promoting and BTIC-suppressing contexts. Our data show cell-type-specific patterns of DNA and histone modifications provide a modulatory layer by determining accessibility of genes to regulation by TGF-β/SMAD3. LBH, one such context-specific target gene, is regulated according to its DNA methylation status and is crucial for TGF-β-dependent promotion of BTICs. Overall, these results reveal that the epigenome plays a central and previously overlooked role in shaping the context-specific effects of TGF-β in cancer..
Bruna, A.
Greenwood, W.
Le Quesne, J.
Teschendorff, A.
Miranda-Saavedra, D.
Rueda, O.M.
Sandoval, J.L.
Vidakovic, A.T.
Saadi, A.
Pharoah, P.
Stingl, J.
Caldas, C.
(2012). TGFβ induces the formation of tumour-initiating cells in claudinlow breast cancer. Nat commun,
Vol.3,
p. 1055.
show abstract
The role of transforming growth factor-beta (TGFβ) in the progression of different molecular subtypes of breast cancer has not been clarified. Here we show that TGFβ increases breast tumour-initiating cell (BTIC) numbers but only in claudin(low) breast cancer cell lines by orchestrating a specific gene signature enriched in stem cell processes that predicts worse clinical outcome in breast cancer patients. NEDD9, a member of the Cas family of integrin scaffold proteins, is necessary to mediate these TGFβ-specific effects through a positive feedback loop that integrates TGFβ/Smad and Rho-actin-SRF-dependent signals. In normal human mammary epithelium, TGFβ induces progenitor activity only in the basal/stem cell compartment, where claudin(low) cancers are presumed to arise. These data show opposing responses to TGFβ in both breast malignant cell subtypes and normal mammary epithelial cell subpopulations and suggest therapeutic strategies for a subset of human breast cancers..
Holland, D.G.
Burleigh, A.
Git, A.
Goldgraben, M.A.
Perez-Mancera, P.A.
Chin, S.-.
Hurtado, A.
Bruna, A.
Ali, H.R.
Greenwood, W.
Dunning, M.J.
Samarajiwa, S.
Menon, S.
Rueda, O.M.
Lynch, A.G.
McKinney, S.
Ellis, I.O.
Eaves, C.J.
Carroll, J.S.
Curtis, C.
Aparicio, S.
Caldas, C.
(2011). ZNF703 is a common Luminal B breast cancer oncogene that differentially regulates luminal and basal progenitors in human mammary epithelium. Embo mol med,
Vol.3
(3),
pp. 167-180.
show abstract
The telomeric amplicon at 8p12 is common in oestrogen receptor-positive (ER+) breast cancers. Array-CGH and expression analyses of 1172 primary breast tumours revealed that ZNF703 was the single gene within the minimal amplicon and was amplified predominantly in the Luminal B subtype. Amplification was shown to correlate with increased gene and protein expression and was associated with a distinct expression signature and poor clinical outcome. ZNF703 transformed NIH 3T3 fibroblasts, behaving as a classical oncogene, and regulated proliferation in human luminal breast cancer cell lines and immortalized human mammary epithelial cells. Manipulation of ZNF703 expression in the luminal MCF7 cell line modified the effects of TGFβ on proliferation. Overexpression of ZNF703 in normal human breast epithelial cells enhanced the frequency of in vitro colony-forming cells from luminal progenitors. Taken together, these data strongly point to ZNF703 as a novel oncogene in Luminal B breast cancer..
Bruna, A.
Darken, R.S.
Rojo, F.
Ocaña, A.
Peñuelas, S.
Arias, A.
Paris, R.
Tortosa, A.
Mora, J.
Baselga, J.
Seoane, J.
(2007). High TGFbeta-Smad activity confers poor prognosis in glioma patients and promotes cell proliferation depending on the methylation of the PDGF-B gene. Cancer cell,
Vol.11
(2),
pp. 147-160.
show abstract
TGFbeta acts as a tumor suppressor in normal epithelial cells and early-stage tumors and becomes an oncogenic factor in advanced tumors. The molecular mechanisms involved in the malignant function of TGFbeta are not fully elucidated. We demonstrate that high TGFbeta-Smad activity is present in aggressive, highly proliferative gliomas and confers poor prognosis in patients with glioma. We discern the mechanisms and molecular determinants of the TGFbeta oncogenic response with a transcriptomic approach and by analyzing primary cultured patient-derived gliomas and human glioma biopsies. The TGFbeta-Smad pathway promotes proliferation through the induction of PDGF-B in gliomas with an unmethylated PDGF-B gene. The epigenetic regulation of the PDGF-B gene dictates whether TGFbeta acts as an oncogenic factor inducing PDGF-B and proliferation in human glioma..