Therapeutic Targeting of Epithelial Mesenchymal Cellular Plasticity in Pancreatic Cancer
Pancreatic ductal adenocarcinoma (PDAC) cells exist on a spectrum of epithelial (E) and quasimesenchymal (QM) transcriptional states with differences in sensitivity to FOLFIRINOX (FFX). GSK-3b is a key regulator PDAC cell epithelial-to-mesenchymal transition (EMT). Here, we performed in vitro analysis of PDAC cell lines combined with multi-omic analysis of data from GSK-3b inhibitor trial (NCT05077800) to evaluate treatment effects on EMT. These data suggested that GSK-3b blockade synergizes with FFX by modulating PDAC plasticity while promoting the development of a tumor suppressive immune microenvironment. Overall design: We performed single-nucleus RNA sequencing on matched pancreatic cancer patient biopsy specimens over the course of treatment with modified FOLFIRINOX, elraglusib, and losartan.