Investigating the role of BRD4-mediated epigenetic programming in the development of pancreatic ductal adenocarcinoma

Pancreatic ductal adenocarcinoma (PDAC) is a highly lethal cancer, with a 5-year survival rate of only 13%. It is projected to become the second leading cause of cancer-related death by 2040. Over 80% of PDACs arise from non-invasive precursor lesions, primarily pancreatic intraepithelial neoplasia (PanIN), through a stepwise accumulation of genetic and epigenetic changes. Activating mutations in KRAS gene, present in over 90% of cases, are recognized as the initiating events in PDAC. However, KRAS alone is inadequate to drive full malignant progression; it requires essential epigenetic and transcription factors to promote PDAC growth and aggressiveness. Among these factors, MYC and the AP-1 transcription factor complex are crucial for mediating KRAS-driven oncogenic programs. Importantly, the epigenetic reader BRD4 plays a significant role by binding to acetylated histones, maintaining high-levels of MYC and AP-1 target gene expression. To investigate how BRD4-mediated epigenetic regulation downstream of mutant KRAS influences PDAC initiation and progression, we performed a pancreas-specific deletion of the epigenetic reader BRD4 in the established KPC (LSL-KrasG12D/+; LSL-Trp53R172H/+; Pdx1-cre) mouse model. Surprisingly, the loss of BRD4 redirected tumorigenesis from the canonical PanIN-PDAC progression route to the intraductal papillary mucinous neoplasm (IPMN) route, leading to invasive PDAC. This finding highlights BRD4 as a critical regulator of pancreatic epithelial lineage under KRAS-driven PDAC malignancy. Histological and transcriptomic analyses revealed that invasive PDACs exhibited hyperactivation of TGF-β1 signaling compared to IPMN lesions in the context of BRD4 loss. Mechanistically, TGF-β1 promoted an epithelial-mesenchymal transition (EMT)-like plasticity and reprogrammed human IPMN cells toward a partially mesenchymal ductal-like state, characterized by co-induction of lineage factors such as SOX9 and aggressive markers like KRT17. Notably, both mouse and human spatial transcriptomic data showed co-upregulation of TGF-β1 and its receptor, TGF-βR2. Pharmacological inhibition or genetic silencing of TGF-βR2 suppressed TGF-β1 expression as well as TGF-β1-mediated EMT plasticity and the invasive phenotype. Together, these findings support a “compensatory overshoot” model, where the loss of BRD4 disrupts the homeostatic regulation of TGF-β1, triggering a self-amplifying TGF-βR2–TGF-β1 autocrine signaling loop that redirects the transition from IPMN to invasive PDAC in KRAS-mediated PDAC models. Our study identifies BRD4 as a gatekeeper of pancreatic epithelial fate, links epigenetic dysregulation to TGF-β1-driven plasticity, and highlights TGF-βR2 as a potential therapeutically actionable target to prevent malignant progression of pre-invasive pancreatic lesions during PDAC development.