Research Interests

Soft Tissue Sarcomas

Soft tissue tumours are a heterogeneous group of mesenchymal tumours that frequently exhibit features of differentiating soft tissues such as striated skeletal muscle (known as rhabdomyosarcomas) and fat (liposarcomas). They account for around 8% of all cancers in childhood and 1% in adults, although the histological spectrum of sarcoma types is different in these age groups. Soft tissue sarcomas are associated with considerable morbidity and mortality.  

Aim: To increase understanding of the underlying molecular biology in rhabdomyosarcomas and liposarcomas that will lead to identifying prognostic markers and more effective therapeutic approaches for individual patients.

Rhabdomyosarcoma  

Rhabdomyosarcomas are the most common paediatric soft-tissue sarcomas accounting for around 5% of all childhood cancers and are a major cause of death from cancer in childhood. Rhabdomyosarcomas express markers indicative of early myogenic development. 

Rhabdomyosarcomas are broadly divided into two main subgroups on the basis of histology; alveolar and embryonal rhabdomyosarcomas.    

A - Alveolar rhabdomyosarcoma –ARMS. This histological micrograph shows an aggressive small round cell tumour. It is so named as it is composed of nests of dissociated cells histologically resembling the air sacs or ‘alveoli’ of the lung. 

B - Embryonal rhabdomyosarcoma – ERMS. This type of rhabdomyosarcoma is a spindle cell tumour, in which the malignant cells resemble varying stages of developing embryonic skeletal muscle.

Alveolar rhabdomyosarcoma are generally associated with a poorer outcome than the embryonal subtype.  Rhabdomyosarcomas harbour many genetic alterations involving particular genes such as genomic amplification events, loss of heterozygosity, gene mutations and translocations that form hybrid genes. Around 70% of alveolar cases contain specific chromosome translocations that usually result in PAX3/FOXO1 or PAX7/FOXO1 gene fusions.

Our recent work has definitively shown that fusion gene negative alveolar rhabdomyosarcomas are clinically and biologically similar to embryonal cases, which has important implications for risk stratification.  We have also demonstrated clear roles for the expression levels of microRNAs influencing the differentiation status of rhabdomyosarcoma cells, with proposed therapeutic potential.    

Current research projects include identifying and validating:

• Prognostic molecular markers derived from mining molecular profiling data.
• Therapeutic targets derived from identifying genes transcriptionally activated by the fusion protein, amplified and/or overexpressed genes and objective target assessment (in collaboration with Bissan Al-Lazikani).
• MicroRNAs that contribute to rhabdomyosarcoma tumour formation including changes to the differentiation status of rhabdomyosarcoma cells 

Our recent investigations have included another type of small round cell tumour that occurs in childhood known as Desmoplastic Small Round Cell Tumour (DSRCT).  

Amplification of MYCN (red) by fluorescence in situ hybridisation and high MYCN expression by immunohistochemistry in nuclei from an alveolar rhabdomyosarcoma patient sample (scale bar 1 and 20 microns, respectively).

We have close links with clinicians in the Paediatric Unit at the Royal Marsden NHS  Trust 

Liposarcomas  

Liposarcomas are a heterogeneous group of tumours that show features of adipocyte differentiation.  Well-differentiated and de-differentiated liposarcomas together comprise the most frequent soft tissue sarcoma in adults.  

A - Well differentiated liposarcoma –WDLPS. This tumour closely recapitulates mature or normal fat, but contains scattered enlarged and abnormal spindle cells. While it is locally aggressive, it can dedifferentiate (below), and acquire the capacity to metastasize. 

B - Dedifferentiated liposarcoma – DDLPS. This tumour is composed of markedly atypical spindle cells and no longer has discernible fatty differentiation on histology. When ‘dedifferentiated,’ the tumour is much more aggressive than its well differentiated counterpart, and is capable of distant metastasis.

Recurrence is frequent, particularly in sites such as the retroperitoneum where mortality in patients approaches 100%.  Only a minority of cases have metastatic spread (15-20%).  Primary liposarcomas generally show a more well-differentiated phenotype than recurrences which increasingly transform towards an undifferentiated appearance.  We are investigating gene/microRNA expression associated with differentiation and recurrence.  This may have implications for predicting, preventing or treating recurrent liposarcomas.

This research is facilitated through links with the Sarcoma Unit at the Royal Marsden NHS Foundation Trust