A Wnt-producing niche drives proliferative potential and progression in lung adenocarcinoma

被引：246

作者：

Tammela, Tuomas ^{[1
]}

Sanchez-Rivera, Francisco J. ^{[1
]}

Cetinbas, Naniye Malli ^{[1
]}

Wu, Katherine ^{[1
]}

Joshi, Nikhil S. ^{[1
]}

Helenius, Katja ^{[1
]}

Park, Yoona ^{[1
]}

Azimi, Roxana ^{[1
]}

Kerper, Natanya R. ^{[1
]}

Wesselhoeft, R. A. Lexander ^{[1
]}

Gu, Xin ^{[1
]}

Schmidt, Leah ^{[1
]}

Cornwall-Brady, Milton ^{[1
]}

Yilmaz, Omer H. ^{[1
]}

Xue, Wen ^{[1
,2
,3
]}

Katajisto, Pekka ^{[4
,5
]}

Bhutkar, Arjun ^{[1
]}

Jacks, Tyler ^{[1
,6
]}

机构：

[1] MIT, David H Koch Inst Integrat Canc Res, Cambridge, MA 02142 USA

[2] Univ Massachusetts, Sch Med, Program Mol Med, RNA Therapeut Inst, Worcester, MA 01605 USA

[3] Univ Massachusetts, Sch Med, Dept Mol Cell & Canc Biol, Worcester, MA 01605 USA

[4] Univ Helsinki, Inst Biotechnol, Helsinki 00014, Finland

[5] Karolinska Inst, Dept Biosci & Nutr, S-14183 Stockholm, Sweden

[6] MIT, Howard Hughes Med Inst, Cambridge, MA 02139 USA

来源：

NATURE | 2017年 / 545卷 / 7654期

关键词：

BETA-CATENIN; TRANSCRIPTIONAL ACTIVATION; TUMOR INITIATION; CANCER; CELL; CRISPR-CAS9; GENERATION; IDENTIFICATION; TUMORIGENESIS; INACTIVATION;

D O I：

10.1038/nature22334

中图分类号：

O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];

学科分类号：

07 ; 0710 ; 09 ;

摘要：

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(1,2). Secreted Wnt signals maintain stem cells in various epithelial tissues, including in lung development and regeneration(3-5). 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.

引用

页码：355 / +

页数：24

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