近日，美国纪念斯隆-凯特琳癌症中心Scott W. Lowe团队的最新工作发现，衰老诱导的血管重塑在胰腺癌中产生治疗靶点。这一研究成果于2020年3月31日在线发表在《细胞》上。
Title: Senescence-Induced Vascular Remodeling Creates Therapeutic Vulnerabilities in Pancreas Cancer
Author: Marcus Ruscetti, John P. Morris, Riccardo Mezzadra, James Russell, Josef Leibold, Paul B. Romesser, Janelle Simon, Amanda Kulick, Yu-jui Ho, Myles Fennell, Jinyang Li, Robert J. Norgard, John E. Wilkinson, Direna Alonso-Curbelo, Ramya Sridharan, Daniel A. Heller, Elisa de Stanchina, Ben Z. Stanger, Charles J. Sherr, Scott W. Lowe
Abstract: KRAS mutant pancreatic ductal adenocarcinoma (PDAC) is characterized by a desmoplasticresponse that promotes hypovascularity, immunosuppression, and resistance to chemo-and immunotherapies. We show that a combination of MEK and CDK4/6 inhibitors thattarget KRAS-directed oncogenic signaling can suppress PDAC proliferation through inductionof retinoblastoma (RB) protein-mediated senescence. In preclinical mouse models ofPDAC, this senescence-inducing therapy produces a senescence-associated secretoryphenotype (SASP) that includes pro-angiogenic factors that promote tumor vascularization,which in turn enhances drug delivery and efficacy of cytotoxic gemcitabine chemotherapy.In addition, SASP-mediated endothelial cell activation stimulates the accumulationof CD8+ T cells into otherwise immunologically “cold” tumors, sensitizing tumors to PD-1checkpoint blockade. Therefore, in PDAC models, therapy-induced senescence can establishemergent susceptibilities to otherwise ineffective chemo- and immunotherapies throughSASP-dependent effects on the tumor vasculature and immune system.