Tammela Tuomas, Sanchez-Rivera Francisco J, Cetinbas Naniye Malli, Wu Katherine, Joshi Nikhil S, Helenius Katja, Park Yoona, Azimi Roxana, Kerper Natanya R, Wesselhoeft R Alexander, Gu Xin, Schmidt Leah, Cornwall-Brady Milton, Yilmaz Ömer H, Xue Wen, Katajisto Pekka, Bhutkar Arjun, Jacks Tyler
David H. Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, Massachusetts 02142, USA.
RNA Therapeutics Institute, Program in Molecular Medicine, and Department of Molecular, Cell and Cancer Biology, University of Massachusetts Medical School, Worcester, Massachusetts 01605, USA.
Nature. 2017 May 18;545(7654):355-359. doi: 10.1038/nature22334. Epub 2017 May 10.
The heterogeneity of cellular states in cancer has been linked to drug resistance, cancer progression and the presence of cancer cells with properties of normal tissue stem cells. Secreted Wnt signals maintain stem cells in various epithelial tissues, including in lung development and regeneration. Here we show that mouse and human lung adenocarcinomas display hierarchical features with two distinct subpopulations, one with high Wnt signalling activity and another forming a niche that provides the Wnt ligand. The Wnt responder cells showed increased tumour propagation ability, suggesting that these cells have features of normal tissue stem cells. Genetic perturbation of Wnt production or signalling suppressed tumour progression. Small-molecule inhibitors targeting essential posttranslational modification of Wnt reduced tumour growth and markedly decreased the proliferative potential of lung cancer cells, leading to improved survival of tumour-bearing mice. These results indicate that strategies for disrupting pathways that maintain stem-like and niche cell phenotypes can translate into effective anti-cancer therapies.
癌症中细胞状态的异质性与耐药性、癌症进展以及具有正常组织干细胞特性的癌细胞的存在有关。分泌的Wnt信号维持各种上皮组织中的干细胞，包括在肺发育和再生过程中。在这里，我们表明小鼠和人类肺腺癌表现出分层特征，具有两个不同的亚群，一个具有高Wnt信号活性，另一个形成提供Wnt配体的生态位。Wnt应答细胞显示出增加的肿瘤增殖能力，表明这些细胞具有正常组织干细胞的特征。Wnt产生或信号传导的基因扰动抑制了肿瘤进展。靶向Wnt必需翻译后修饰的小分子抑制剂减少了肿瘤生长，并显著降低了肺癌细胞的增殖潜力，从而提高了荷瘤小鼠的存活率。这些结果表明，破坏维持干细胞样和生态位细胞表型的信号通路的策略可以转化为有效的抗癌疗法。
