Super-Enhancer modules controlling plasticity and response to therapy in pancreatic cancer
Recently discovered subtypes in pancreatic ductal adenocarcinoma (PDAC) have potential to better guide the choice of therapy. However, this is challenged by the lack of robust data, patient heterogeneity, tumour cell plasticity, dynamic crosstalk with surrounding cells, and post-chemotherapy induced alterations. A few transcription factors may act as drivers of specific PDAC subtypes and changes in there expression through aberrant activation of super-enhancers may lead to ‘’subtype switching’’. However, the effect of the tumour-microenvironment on enhancer-driven gene expression programme to promote ‘’subtype switching’’ in pancreatic tumour cells remains largely unexplored. Hence, with this proposal I aim to provide in-depth characterization of this dynamic crosstalk combining reporter tracing through fluorescent labelling of subtype-specific transcriptional drivers of tumour cell states with powerful high throughput single-cell technologies, and super-enhancer single cell profiling which will translate to a clinical study of neoadjuvant chemotherapy with sequential tumour sample profiling. This work will ultimately provide a platform for the development of methods to precisely determine the ""phenotypic"" state of PDAC cells and aid in designing new agents to target these processes, with the ultimate goal of converting non-responder to responder tumours and improve patient outcome.