信号转导及转录激活因子3/整合素轴加速胰腺癌的起始和进展。

A STAT3/integrin axis accelerates pancreatic cancer initiation and progression.

作者信息

Campos Alejandro D, Shepard Ryan M, Ortega Zachary, Heumann Ingrid, Wilke Anna E, Nam Arin, Cable Carson, Kouhmareh Kourosh, Klemke Richard, Mattson Nicole M, Ideker Trey, De Arruda Saldanha Camila, Heinz Sven, Weaver Valerie, Von Schalscha Tami, Wettersten Hiromi I, Weis Sara M, Cheresh David A

机构信息

Department of Pathology, Moores Cancer Center at the University of California San Diego, La Jolla, San Diego, CA, USA; Department of Pathology, Sanford Consortium for Regenerative Medicine at the University of California San Diego, La Jolla, San Diego, CA, USA.

Division of Genomics and Precision Medicine, Department of Medicine, University of California San Diego, La Jolla, San Diego, CA, USA.

出版信息

Cell Rep. 2025 Aug 26;44(8):116010. doi: 10.1016/j.celrep.2025.116010. Epub 2025 Jul 22.

DOI:10.1016/j.celrep.2025.116010

PMID:40701148

Abstract

The signal transducer and activator of transcription 3 (STAT3) pathway drives pancreatic ductal adenocarcinoma (PDAC) progression by coordinating cellular responses to stress and inflammation. We perform ChIP-seq on hypoxia- or oncostatin-M-treated PDAC cells to identify sites at which phospho-STAT3 binds to regulate the expression of genes linked to poor survival. A top hit among these is ITGB3, which we show promotes PDAC initiation and progression. Single-cell transcriptomics reveal that ITGB3 expression is enriched in PDAC cells experiencing oxidative stress due to chemotherapy. Moreover, high ITGB3 expression positively correlates with STAT3 signaling, hypoxia, and the basal subtype. Mechanistically, chromatin accessibility at ITGB3 enhancers controls STAT3's ability to induce ITGB3 expression, illuminating a plastic regulatory mechanism modulating STAT3 activity. Leveraging this insight, we identify additional STAT3 target genes regulated similarly to ITGB3 to establish an 18-gene signature involved in adaptive responses and able to stratify survival outcomes. Collectively, these findings highlight a novel opportunity to stratify PDAC subpopulations for STAT3-targeted therapies.

摘要

信号转导与转录激活因子3（STAT3）通路通过协调细胞对应激和炎症的反应来驱动胰腺导管腺癌（PDAC）的进展。我们对缺氧或抑瘤素-M处理的PDAC细胞进行染色质免疫沉淀测序（ChIP-seq），以确定磷酸化STAT3结合调控与不良生存相关基因表达的位点。其中最显著的是整合素β3（ITGB3），我们发现它促进PDAC的起始和进展。单细胞转录组学显示，ITGB3表达在因化疗而经历氧化应激的PDAC细胞中富集。此外，高ITGB3表达与STAT3信号传导、缺氧和基底亚型呈正相关。从机制上讲，ITGB3增强子处的染色质可及性控制STAT3诱导ITGB3表达的能力，揭示了一种调节STAT3活性的可塑性调控机制。利用这一见解，我们鉴定出与ITGB3类似受STAT3调控的其他靶基因，以建立一个涉及适应性反应且能够对生存结果进行分层的18基因特征。总的来说，这些发现凸显了为针对STAT3的疗法对PDAC亚群进行分层的新机会。