Tumour cell heterogeneity maintained by cooperating subclones in Wnt-driven mammary cancers.
Tumour cell heterogeneity maintained by cooperating subclones in Wnt-driven mammary cancers.
复制标题
作者：
癌症基因组测序研究表明，单个乳腺癌通常含有多个遗传上不同的亚克隆。由于癌变涉及细胞-细胞合作的破坏，通常维持上皮组织结构，恶性微环境中的个体亚克隆通常被描述为自私的竞争者。或者，乳腺癌亚克隆可能相互合作，在某些情况下获得选择性生长优势。虽然克隆间合作已被证明是推动果蝇模型中的肿瘤发生，但缺乏哺乳动物上皮肿瘤细胞亚克隆之间功能合作的明确证据。在这里，我们使用小鼠乳腺癌模型，以表明克隆间的合作可能是必要的肿瘤维持。分泌的信号分子Wnt 1的异常表达产生由基底和管腔肿瘤细胞亚型组成的混合谱系乳腺肿瘤，其据称源自位于肿瘤细胞层级顶部的双能恶性祖细胞。使用体细胞Hrasmutations作为克隆标记，我们发现，一些Wnt肿瘤确实符合一个层次的配置，但其他人出乎意料的海港基因不同basalHrasmutant和luminalHraswild-type亚克隆。这两个亚克隆都是有效的肿瘤繁殖所必需的，这严格依赖于管腔产生的Wnt 1。当双克隆肿瘤用Wnt撤回来模拟靶向治疗时，肿瘤消退和复发的分析显示，基础亚克隆招募异源Wnt产生细胞来恢复肿瘤生长。或者，在缺乏替代Wnt来源的情况下，原始亚克隆通常通过恢复合作或切换到叛逃者策略来进化以拯救Wnt途径激活并驱动复发。发现人类癌症中类似的克隆间合作模式可能会为旨在根除肿瘤细胞群落的努力提供信息。
Cancer genome sequencing studies indicate that a single breast cancer typically harbours multiple genetically distinct subclones,,,. As carcinogenesis involves a breakdown in the cell–cell cooperation that normally maintains epithelial tissue architecture, individual subclones within a malignant microenvironment are commonly depicted as self-interested competitors,. Alternatively, breast cancer subclones might interact cooperatively to gain a selective growth advantage in some cases. Although interclonal cooperation has been shown to drive tumorigenesis in fruitfly models,, definitive evidence for functional cooperation between epithelial tumour cell subclones in mammals is lacking. Here we use mouse models of breast cancer to show that interclonal cooperation can be essential for tumour maintenance. Aberrant expression of the secreted signalling molecule Wnt1 generates mixed-lineage mammary tumours composed of basal and luminal tumour cell subtypes, which purportedly derive from a bipotent malignant progenitor cell residing atop a tumour cell hierarchy. Using somaticHrasmutations as clonal markers, we show that some Wnt tumours indeed conform to a hierarchical configuration, but that others unexpectedly harbour genetically distinct basalHrasmutant and luminalHraswild-type subclones. Both subclones are required for efficient tumour propagation, which strictly depends on luminally produced Wnt1. When biclonal tumours were challenged with Wnt withdrawal to simulate targeted therapy, analysis of tumour regression and relapse revealed that basal subclones recruit heterologous Wnt-producing cells to restore tumour growth. Alternatively, in the absence of a substitute Wnt source, the original subclones often evolve to rescue Wnt pathway activation and drive relapse, either by restoring cooperation or by switching to a defector strategy. Uncovering similar modes of interclonal cooperation in human cancers may inform efforts aimed at eradicating tumour cell communities.
登录
查看更多内容
影响因子：
64.8
作者：
通讯作者：
--
影响因子：
64.8
作者：
Greaves, Mel;Maley, Carlo C.
通讯作者：
Maley, Carlo C.
影响因子：
10.5
作者：
Inda, Maria-del-Mar;Bonavia, Rudy;Furnari, Frank
通讯作者：
Furnari, Frank
影响因子：
12.3
作者：
Herschkowitz JI;Simin K;Weigman VJ;Mikaelian I;Usary J;Hu Z;Rasmussen KE;Jones LP;Assefnia S;Chandrasekharan S;Backlund MG;Yin Y;Khramtsov AI;Bastein R;Quackenbush J;Glazer RI;Brown PH;Green JE;Kopelovich L;Furth PA;Palazzo JP;Olopade OI;Bernard PS;Churchill GA;Van Dyke T;Perou CM
通讯作者：
Perou CM
影响因子：
64.8
作者：
Navin N;Kendall J;Troge J;Andrews P;Rodgers L;McIndoo J;Cook K;Stepansky A;Levy D;Esposito D;Muthuswamy L;Krasnitz A;McCombie WR;Hicks J;Wigler M
通讯作者：
Wigler M