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.

胰腺导管腺癌（Pancreatic ductal adenocarcinoma, PDAC）细胞处于上皮（E）与准间质（QM）转录状态的连续谱系中，其对FOLFIRINOX（FFX）的化疗敏感性存在显著差异。糖原合酶激酶3β（GSK-3β）是调控PDAC细胞上皮间质转化（epithelial-to-mesenchymal transition, EMT）的关键调节因子。本研究针对PDAC细胞系开展体外实验分析，并结合GSK-3β抑制剂临床试验（NCT05077800）的多组学数据，评估该干预手段对EMT的调控效应。研究结果显示，GSK-3β阻断可通过调节PDAC细胞可塑性，并促进肿瘤抑制性免疫微环境的构建，从而与FFX产生协同治疗效果。整体实验设计：本研究对接受改良型FOLFIRINOX方案、elraglusib及氯沙坦（losartan）治疗的配对胰腺癌患者活检样本，进行单细胞核RNA测序。