癌症研究
生物
转移
胰腺癌
基因敲除
肿瘤进展
转移抑制因子
肿瘤微环境
抑制器
癌症
细胞培养
遗传学
肿瘤细胞
作者
Camino Bermejo‐Rodríguez,Joaquín Araos Henríquez,Giuseppina Caligiuri,Sara Pinto Teles,Youngkyu Park,A.G. Evans,Lawrence N. Barrera,Albrecht Neeße,Robert Grützmann,Daniela E. Aust,Petra Rümmele,Thomas Knösel,Masako Narita,Masashi Narita,Fiona Campbell,Daniel Öhlund,Christian Pilarsky,Lukas E. Dow,Patrick O. Humbert,Giulia Biffi,David A. Tuveson,Pedro A. Pérez–Mancera
出处
期刊:Cancer Research
[American Association for Cancer Research]
日期:2024-07-22
标识
DOI:10.1158/0008-5472.can-23-3419
摘要
Abstract Perturbation of cell polarity is a hallmark of pancreatic ductal adenocarcinoma (PDAC) progression. Scribble (SCRIB) is a well characterized polarity regulator that has diverse roles in the pathogenesis of human neoplasms. To investigate the impact of SCRIB deficiency on PDAC development and progression, Scrib was genetically ablated in well-established mouse models of PDAC. Scrib loss in combination with KrasG12D did not influence development of pancreatic intraepithelial neoplasms (PanIN) in mice. However, Scrib deletion cooperated with KrasG12D and concomitant Trp53 heterozygous deletion to promote invasive PDAC and metastatic dissemination, leading to reduced overall survival. Immunohistochemical and transcriptome analyses revealed that Scrib-null tumors display a pronounced reduction of collagen content and cancer associated fibroblast (CAF) abundance. Mechanistically, interleukin 1α (IL1α) levels were reduced in Scrib deficient tumors, and Scrib knockdown downregulated IL1α in mouse PDAC organoids (mPDOs), which impaired CAF activation. Furthermore, Scrib loss increased YAP activation in mPDOs and established PDAC cell lines, enhancing cell survival. Clinically, SCRIB expression was decreased in human PDAC, and SCRIB mislocalization was associated with poorer patient outcome. These results indicate that SCRIB deficiency enhances cancer cell survival and remodels the tumor microenvironment to accelerate PDAC development and progression, establishing the tumor suppressor function of SCRIB in advanced pancreatic cancer.
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