Differentiation-state plasticity is a targetable resistance mechanism in basal-like breast cancer.
Differentiation-state plasticity is a targetable resistance mechanism in basal-like breast cancer.
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DOI：
10.1038/s41467-018-05729-w
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发表时间：
2018-09-19
影响因子：
16.6
通讯作者：
Sears RC
中科院分区：
文献类型：
--
作者：
Risom T;Langer EM;Chapman MP;Rantala J;Fields AJ;Boniface C;Alvarez MJ;Kendsersky ND;Pelz CR;Johnson-Camacho K;Dobrolecki LE;Chin K;Aswani AJ;Wang NJ;Califano A;Lewis MT;Tomlin CJ;Spellman PT;Adey A;Gray JW;Sears RC
肿瘤内的异质性来自基因组的不稳定性和表观基因组的可塑性，并与细胞毒性和靶向治疗的耐药性有关。我们在这里表明，细胞状态的异质性，定义为分化状态标志物的表达，是高的三阴性和基底样乳腺癌亚型，并与改变标志物表达的耐药持续（DTP）细胞群体出现在治疗过程中与广泛的通路靶向治疗化合物。我们发现，MEK和PI 3 K/mTOR的信使驱动的DTP状态出现通过不同的细胞状态的转换，而不是达尔文的选择预先存在的亚群，这些转换涉及动态重塑开放的染色质结构。在DTP细胞中观察到许多染色质修饰酶（包括BRD 4）的活性增加。用PI 3 K/mTOR抑制剂BEZ 235和BET抑制剂JQ 1共处理防止开放染色质结构的变化，抑制DTP状态的获得，并导致体外稳健的细胞死亡和体内异种移植物消退。肿瘤内异质性可导致对治疗的抵抗。在这里，作者表明，药物耐受性持久的细胞群体出现在治疗过程中，这些新兴的群体通过表观遗传介导的细胞状态转变，而不是亚群选择。
Intratumoral heterogeneity in cancers arises from genomic instability and epigenomic plasticity and is associated with resistance to cytotoxic and targeted therapies. We show here that cell-state heterogeneity, defined by differentiation-state marker expression, is high in triple-negative and basal-like breast cancer subtypes, and that drug tolerant persister (DTP) cell populations with altered marker expression emerge during treatment with a wide range of pathway-targeted therapeutic compounds. We show that MEK and PI3K/mTOR inhibitor-driven DTP states arise through distinct cell-state transitions rather than by Darwinian selection of preexisting subpopulations, and that these transitions involve dynamic remodeling of open chromatin architecture. Increased activity of many chromatin modifier enzymes, including BRD4, is observed in DTP cells. Co-treatment with the PI3K/mTOR inhibitor BEZ235 and the BET inhibitor JQ1 prevents changes to the open chromatin architecture, inhibits the acquisition of a DTP state, and results in robust cell death in vitro and xenograft regression in vivo. Resistance to therapy can be driven by intratumoral heterogeneity. Here, the authors show that drug tolerant persistent cell populations emerge during treatment, and these emergent populations arise through epigenetically mediated cell state transitions rather than sub population selection.
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影响因子：
12.3
作者：
Carpenter AE;Jones TR;Lamprecht MR;Clarke C;Kang IH;Friman O;Guertin DA;Chang JH;Lindquist RA;Moffat J;Golland P;Sabatini DM
通讯作者：
Sabatini DM
影响因子：
3.7
作者：
Chu IM;Lai WC;Aprelikova O;El Touny LH;Kouros-Mehr H;Green JE
通讯作者：
Green JE
影响因子：
16.6
作者：
Gascard, Philippe;Bilenky, Misha;Sigaroudinia, Mahvash;Zhao, Jianxin;Li, Luolan;Carles, Annaick;Delaney, Allen;Tam, Angela;Kamoh, Baljit;Cho, Stephanie;Griffith, Malachi;Chu, Andy;Robertson, Gordon;Cheung, Dorothy;Li, Irene;Heravi-Moussavi, Alireza;Moksa, Michelle;Mingay, Matthew;Hussainkhel, Angela;Davis, Brad;Nagarajan, Raman P.;Hong, Chibo;Echipare, Lorigail;O'Geen, Henriette;Hangauer, Matthew J.;Cheng, Jeffrey B.;Neel, Dana;Hu, Donglei;McManus, Michael T.;Moore, Richard;Mungall, Andrew;Ma, Yussanne;Plettner, Patrick;Ziv, Elad;Wang, Ting;Farnham, Peggy J.;Jones, Steven J. M.;Marra, Marco A.;Tlsty, Thea D.;Costello, Joseph F.;Hirst, Martin
通讯作者：
Hirst, Martin
影响因子：
64.5
作者：
Gupta PB;Onder TT;Jiang G;Tao K;Kuperwasser C;Weinberg RA;Lander ES
通讯作者：
Lander ES
影响因子：
4.3
作者：
Banelli, Barbara;Carra, Elisa;Romani, Massimo
通讯作者：
Romani, Massimo