衰老誘導(dǎo)的血管重塑在胰腺癌中產(chǎn)生治療靶點
近日，美國紀(jì)念斯隆-凱特琳癌癥中心Scott W. Lowe團(tuán)隊的工作發(fā)現(xiàn)，衰老誘導(dǎo)的血管重塑在胰腺癌中產(chǎn)生治療靶點。這一研究成果于2020年3月31日在線發(fā)表在《細(xì)胞》上。
研究人員發(fā)現(xiàn)，靶向KRAS介導(dǎo)致癌信號的MEK和CDK4/6抑制劑聯(lián)用可以通過誘導(dǎo)視網(wǎng)膜母細(xì)胞瘤（RB）蛋白介導(dǎo)的衰老來抑制胰腺導(dǎo)管腺癌（PDAC）增殖。在PDAC的臨床前小鼠模型中，這種誘導(dǎo)衰老的療法產(chǎn)生了一種衰老相關(guān)的分泌表型（SASP），其中包括促腫瘤血管生成的促血管生成因子，從而增強(qiáng)了藥物的遞送和細(xì)胞毒性吉西他濱化療的功效。
此外，SASP介導(dǎo)的內(nèi)皮細(xì)胞活化刺激CD8+T細(xì)胞積聚成免疫原性的“冷”腫瘤，使腫瘤對PD-1檢查點阻斷敏感。因此，在PDAC模型中，治療引起的衰老可以通過對腫瘤脈管系統(tǒng)和免疫系統(tǒng)的SASP依賴性作用，建立起對其他無效的化學(xué)和免疫療法的敏感性。
據(jù)介紹，KRAS突變型PDAC的特征在于具有促增生作用，可促進(jìn)血流不足，免疫抑制以及對化學(xué)療法和免疫療法的抵抗力。
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
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