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衰老诱导的血管重塑在胰腺癌中产生治疗靶点
2020-04-01 17:11

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。

研究人员发现,靶向KRAS介导致癌信号的MEK和CDK4/6抑制剂联用可以通过诱导视网膜母细胞瘤(RB)蛋白介导的衰老来抑制胰腺导管腺癌(PDAC)增殖。在PDAC的临床前小鼠模型中,这种诱导衰老的疗法产生了一种衰老相关的分泌表型(SASP),其中包括促肿瘤血管生成的促血管生成因子,从而增强了药物的递送和细胞毒性吉西他滨化疗的功效。
 
此外,SASP介导的内皮细胞活化刺激CD8+T细胞积聚成免疫原性的“冷”肿瘤,使肿瘤对PD-1检查点阻断敏感。因此,在PDAC模型中,治疗引起的衰老可以通过对肿瘤脉管系统和免疫系统的SASP依赖性作用,建立起对其他无效的化学和免疫疗法的敏感性。
 
据介绍,KRAS突变型PDAC的特征在于具有促增生作用,可促进血流不足,免疫抑制以及对化学疗法和免疫疗法的抵抗力。
 
附:英文原文

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

Issue&Volume: 2020-03-31

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.

DOI: 10.1016/j.cell.2020.03.008

Source: https://www.cell.com/cell/fulltext/S0092-8674(20)30270-1

Cell:《细胞》,创刊于1974年。隶属于细胞出版社,最新IF:66.85
官方网址:https://www.cell.com/
投稿链接:https://www.editorialmanager.com/cell/default.aspx

本期文章:《细胞》:Online/在线发表

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