小柯机器人

利用进化关系预测黑色素瘤的抗药性
2021-06-20 16:32

比利时癌症生物学中心Jean-Christophe Marine和Florian Rambow小组合作的最新研究利用进化关系预测了黑色素瘤细胞对抗癌药物的遗传与非遗传抗性。相关论文在线发表在2021年6月17日出版的《癌细胞》杂志上。

研究表明在使用丝裂剂激活蛋白激酶治疗的黑色素瘤细胞中,其最小残留疾病(MRD)抗性产生过程中,瞬态神经嵴干细胞(NCSC)群的出现受环境影响。这种增加依赖于胶质细胞衍生的神经营养因子依赖性信号级联,其以局灶性粘合激酶(FAK)依赖的方式激活AKT信号途径。通过抑制FAK消除NCSC细胞群可以阻碍患者来源肿瘤异种移植物的复发。

令人惊讶的是,最终对该治疗产生免疫的所有肿瘤都具有赋予抵的遗传改变,并增加对细胞外信号调节激酶抑制的敏感性。这些发现揭示了一种消除黑色素瘤非遗传耐药性的方法,并证明MRD的细胞组成决定了不同耐药的产生途径。

据了解,治疗抗性来源于非均相耐药性细胞存留或通过遗传和非遗传机制产生的MRD。急需阐明是否MRD中存在某些特定分子决定了这两种不同耐药机制哪个占主导地位。

附:英文原文

Title: Evolutionary predictability of genetic versus nongenetic resistance to anticancer drugs in melanoma

Author: Oskar Marin-Bejar, Aljosja Rogiers, Michael Dewaele, Julia Femel, Panagiotis Karras, Joanna Pozniak, Greet Bervoets, Nina Van Raemdonck, Dennis Pedri, Toon Swings, Jonas Demeulemeester, Sara Vander Borght, Stefan Lehnert, Francesca Bosisio, Joost J. van den Oord, Isabelle Vanden Bempt, Diether Lambrechts, Thierry Voet, Oliver Bechter, Helen Rizos, Mitchell P. Levesque, Eleonora Leucci, Amanda W. Lund, Florian Rambow, Jean-Christophe Marine

Issue&Volume: 2021-06-17

Abstract: Therapy resistance arises from heterogeneous drug-tolerant persister cells or minimalresidual disease (MRD) through genetic and nongenetic mechanisms. A key question iswhether specific molecular features of the MRD ecosystem determine which of thesetwo distinct trajectories will eventually prevail. We show that, in melanoma exposedto mitogen-activated protein kinase therapeutics, emergence of a transient neuralcrest stem cell (NCSC) population in MRD concurs with the development of nongeneticresistance. This increase relies on a glial cell line-derived neurotrophic factor-dependentsignaling cascade, which activates the AKT survival pathway in a focal adhesion kinase(FAK)-dependent manner. Ablation of the NCSC population through FAK inhibition delaysrelapse in patient-derived tumor xenografts. Strikingly, all tumors that ultimatelyescape this treatment exhibit resistance-conferring genetic alterations and increasedsensitivity to extracellular signal-regulated kinase inhibition. These findings identifyan approach that abrogates the nongenetic resistance trajectory in melanoma and demonstratethat the cellular composition of MRD deterministically imposes distinct drug resistanceevolutionary paths.

DOI: 10.1016/j.ccell.2021.05.015

Source: https://www.cell.com/cancer-cell/fulltext/S1535-6108(21)00281-6

Cancer Cell:《癌细胞》,创刊于2002年。隶属于细胞出版社,最新IF:23.916
官方网址:https://www.cell.com/cancer-cell/home
投稿链接:https://www.editorialmanager.com/cancer-cell/default.aspx


本期文章:《癌细胞》:Online/在线发表

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