Defining the Core Gene Regulatory Network of PDAC cell Identity

Abstract

Pancreatic cancer is one of the deadliest forms of cancer and is the sixth leading cause of cancer-related deaths. The most common type of pancreatic cancer is pancreatic ductal adenocarcinoma (PDAC), which originates in the exocrine pancreas and accounts for the majority of pancreatic cancer cases. PDAC is aggressive, rapidly advancing from asymptomatic stages to metastatic disease in most patients. Due to the limited treatment options available, which currently only address a small subset of PDAC cases and the expected rise in PDAC incidence in the coming years, there is an urgent need for early diagnosis at treatable stages. To meet this demand, numerous studies have focused on identifying early diagnostic markers, understanding disease progression, and developing novel treatment approaches. Yet, the PDAC regulatory network that drives its progression remains elusive. This is partly due to the heterogeneity of PDAC and a lack of appropriate controls. In this project, I aim to define the core regulatory network of PDAC using patient-derived xenograft to specifically enrich the aggressive squamous basal-like PDAC type. As a control, I used normal pancreatic exocrine-enriched samples derived from healthy donors. This enabled a comprehensive comparison between PDAC transcriptome and chromatin landscape and normal exocrine cells. Using ChIP-seq, I reveal that PITX1 in combination with other TFs act as master regulators that control PDAC-specific gene expression. Loss of function of PITX1 confirms its crucial role in promoting PDAC cell proliferation and tumour progression. Furthermore, I show that PITX1 sustain PDAC cell identity, by resisting reprogramming to induced pluripotency. Overall, my findings provide a deep insight into the core gene regulatory network of PDAC that is responsible for the disease progression and reoccurrence.