Abstract A094: Mapping early Pancreatic Cancer evolution through enhancer reprogramming and transcription factor interactomes
Paula D. Santos, Lisa Young, Sarah Baloul, Charlotte Simpson, Cathrin Graewe, Kamal Kishore, Tim Halim, Alasdair Russell, Sean Flynn, Igor Chernukhin, Jason Carroll, Anita Balakrishnan, Shalini V. RaoAbstract
Background:
Pancreatic ductal adenocarcinoma (PDAC) remains one of the deadliest malignancies, with poor survival largely driven by late-stage diagnosis. Approximately 85% of patients present with advanced disease, limiting curative treatment options. A major challenge in PDAC is the absence of biomarkers capable of identifying individuals at risk during early disease (ED). While oncogenic driver mutations initiate pancreatic tumorigenesis, the molecular switch that drives progression from pre-invasive pancreatic intraepithelial neoplasia (PanIN) to invasive PDAC remains poorly understood. Emerging evidence suggests that lineage-defining transcription factors (TFs) regulate tumor evolution through enhancer reprogramming, altered chromatin organization, and remodeling of regulatory complexes. However, how context-specific regulatory elements and TF networks emerge during early pancreatic tumorigenesis remains unclear.
Methods:
To investigate early pancreatic tumorigenesis, we established and characterized a panel of PanIN cell lines derived from Ptf1a-Cre;KrasG12D (KC) mice. Integrated 3D-chromatin accessibility, TF binding, and transcriptomic profiling were used to identify stage-specific regulatory landscapes and lineage-defining transcriptional networks associated with PanIN-to-PDAC progression. qPLEX-RIME (Rapid Immunoprecipitation Mass spectrometry of Endogenous proteins) was applied to generate unbiased TF interactome maps in PanIN models and human PDAC specimens. These datasets were integrated to develop a barcoded cDNA library of candidate lineage-defining TFs for functional interrogation.
Results:
Chromatin accessibility profiling revealed progressive enhancer reprogramming during PanIN-to-PDAC transition, with dynamic gains and losses of regulatory regions associated with altered TF activity and gene regulatory network rewiring. Differential TF binding analyses identified lineage-defining TFs selectively enriched during malignant progression, implicating these regulators in the establishment of PDAC-specific cellular states. qPLEX-RIME profiling of (E.g. FOXA1, GATA6 and HNF4G) demonstrated distinct chromatin-associated protein complexes in murine PanIN models and human clinical samples, revealing differential enrichment of TF-associated regulatory complexes between early disease and PDAC. These findings define candidate regulatory complexes that may drive enhancer reprogramming and malignant transformation. Functional interrogation using the barcoded TF library is ongoing to determine the causal contribution of these regulators to PDAC progression.
Conclusions:
These findings support a model in which enhancer reprogramming and lineage-specific TF complexes act as key determinants of the transition from pre-invasive PanIN lesions to invasive PDAC. Mapping these regulatory networks provides a framework for identifying early disease biomarkers, improving risk stratification of pancreatic lesions, and uncovering context-specific therapeutic vulnerabilities in pancreatic cancer.
Citation Format:
Paula D. Santos, Lisa Young, Sarah Baloul, Charlotte Simpson, Cathrin Graewe, Kamal Kishore, Tim Halim, Alasdair Russell, Sean Flynn, Igor Chernukhin, Jason Carroll, Anita Balakrishnan, Shalini V. Rao. Mapping early Pancreatic Cancer evolution through enhancer reprogramming and transcription factor interactomes [abstract]. In: Proceedings of the AACR Conference on Pancreatic Cancer: New Frontiers in Biology and Therapeutic Development; 2026 Sep 25-28; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2026;86(18_Suppl_2):Abstract nr A094.