SP2: Characterizing subtype-specific adaptation to epigenetic therapy in PDAC

The heterogeneity of the neoplastic epithelium and the stromal microenvironment presents significant challenges in treating PDAC. Our previous studies have revealed that there are two clinically relevant subtypes of PDAC: the chemotherapy-responsive classical (CLA) subtype and the therapy-resistant basal-like (BL) subtype. These subtypes are controlled by lineage-specific transcription factors (TFs) and their associated chromatin regulators. However, the impact of these subtype-specific TFs and epigenetic regulators on therapy outcomes remains largely unclear. In this SP2 project, the labs of Argyris Papantonis and Shiv K. Singh propose that lineage-specific TFs, along with their associated chromatin-modifying cofactors such as HDACs and BRDs, play a crucial role in determining therapy resistance. We hypothesize that these factors contribute to resistance through mechanisms influenced by cellular plasticity and adaptation.

To investigate this hypothesis, the PhD- (Papantonis group) and MD- (Singh group) candidates of the first cohort will examine how lineage TFs and epigenetic cofactors establish subtype specificity in response to epigenetic therapies (such as HDAC inhibitors and BET inhibitors) by analyzing long-range enhancer-promoter interactions. This will involve techniques such as Micro-C, chromatin accessibility assays (i.e., ATAC-seq), and assessments of TF binding changes (e.g., ChIP or CUT&Tag) using PDAC cell lines and patient-derived organoids (PDOs). Additionally, they will evaluate cellular plasticity and resistance to subclass-specific HDAC inhibitors and BET inhibitors using both in vitro models and patient samples. The PhD- (Singh group) and MD- (Papantonis group) candidates of the second cohort will employ in vivo orthotopic models, utilizing a combination of single-cell genomics (i.e., scRNA-seq and scATAC-seq) and quantitative multiplex imaging to explore regulatory changes in both tumor and stromal compartments in response to epigenetic therapies. They will further assess and target both intrinsic and extrinsic adaptations driven by epigenetic inhibitors by co-treating in vitro and in vivo models with standard chemotherapeutics. Collectively, this research aims to leverage the inherent plasticity of PDAC entities to develop tailored therapeutic approaches.