Abstract A043: p53 licenses transcriptional regulation by TEAD to dictate cell fate in pancreatic ductal adenocarcinoma

Activity of the tumor suppressor p53 defines the pre-malignant to malignant transition in more than half of pancreatic ductal adenocarcinoma (PDAC). How p53 determines these molecularly distinct expression and cell fate landscapes remains poorly understood. Here, we demonstrate that p53-dependent gene expression programs and resultant metaplastic heterogeneity are determined by regulation of TEAD transcriptional complex activity at multiple levels of molecular control. p53 activity in pancreatic cancer cells expands transcriptional regulation by TEAD by reorganizing its binding at newly accessible enhancer landscapes, resulting in distinct TEAD-driven gene regulatory networks triggered by p53. While TEAD and p53 cooperate to drive secretory programs involved in tumor-microenvironment communication, TEAD concurrently antagonizes metaplastic differentiation states facilitated by p53. p53 promotes expression of gastric pit-like (GPL) differentiation markers associated with the classical subtype of PDAC that are broadly repressed by TEAD activity in vitro and in vivo. GPL differentiation is acutely sensitive to physiological cues regulating the TEAD coactivators YAP and TAZ including genetic perturbation of the Hippo pathway, senescence associated actin dynamics, cell-to-cell contact, and adaptive YAP/TAZ accumulation in response to clinically relevant inhibitors of the Ras/MAPK pathway. GPL/classical differentiation inversely correlates with TEAD activity in human PDAC samples and potent TEAD inhibition in human pancreatic cancer cells drives a shift toward GPL and classical cell fate. Taken together, our work implicates coordination of TEAD transcriptional regulation by p53 as a determinant of molecular heterogeneity during pancreatic cancer progression. Citation Format: Cole P. Martin, Scott Bang, William Sullivan, Joseph R. Gomes, Yusha Liu, Matthew Smith, A. Cole. Edwards, Channing Der, John P. Morris IV. p53 licenses transcriptional regulation by TEAD to dictate cell fate in pancreatic ductal adenocarcinoma [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Advances in Pancreatic Cancer Research—Emerging Science Driving Transformative Solutions; Boston, MA; 2025 Sep 28-Oct 1; Boston, MA. Philadelphia (PA): AACR; Cancer Res 2025;85(18_Suppl_3):Abstract nr A043.