Understanding oncogenic transcriptional processes in synovial sarcoma
Worldwide Cancer Research
Trinity College Dublin
Synovial sarcoma is an often aggressive malignancy primarily effecting children and young adults. Unfortunately, these tumours often do not respond well to conventional therapeutic interventions and overall survival rates remain poor. The disease is caused by a recurrent chromosomal translocation generating a characteristic fusion protein, SS18-SSX. In synovial sarcoma cells the fusion protein assembles into SWI/SNF complexes, which are essential chromatin regulators that alter chromatin structure to regulate gene expression. Incorporation of SS18-SSX into these complexes alters their function, resulting in significant oncogenic gene expression changes. Targeting the oncogenic function of SS18-SSX presents and attractive therapeutic option for the development of mechanistically anchored cancer treatments; however the fusion itself has proven intractable for direct targeting. Here, we are pursuing a research program aimed at better understanding the function of SS18-SSX containing complexes and exploring new opportunities to therapeutically target complexes containing the fusion protein. Using CRISPR/Cas9 based approaches in functional genomics screening we’ve identified the acetyltransferase enzyme p300 as functionally essential in synovial sarcoma cells. By combining these data with in depth proteomic analyses of SS18-SSX interacting proteins we further identified that p300 physically associates with SS18-SSX. In Aims 1 and 2 of this research program we are combining biochemical and genomics approaches to characterise the composition and function of SS18-SSX/p300 containing complexes in synovial sarcoma cells. In Aim 3 we are taking an ambitious approach combining CRISPR/Cas9 screening with single-cell genomics analysis platforms to characterise the molecular function of SS18-SSX containing complexes in cancer cells. Together, these aims will provide a mechanistic understanding and potential therapeutic rationale for targeting p300 function as a novel therapy in patients. In addition to providing unprecedented molecular understanding of disease biology, which will likely highlight more opportunities to explore and develop future approaches to more effectively treat synovial sarcoma patients.
2.1 Biological and endogenous factors