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

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

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....

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Bibliographic Details
Main Authors: Katajisto, Pekka, Tammela, Tuomas, Cetinbas, Naniye, Wu, Katherine, Helenius, Katja Piritta, Park, Yoona K, Azimi, Roxana S., Kerper, Natanya R., Wesselhoeft IV, Robert Alexander, Gu, Xin, Schmidt, Leah Marie, Cornwall-Brady, Milton R., Yilmaz, Omer, Xue, Wen, Bhutkar, Arjun, Jacks, Tyler E, Sanchez-Rivera, Francisco Jav, Joshi, Nik
Other Authors: Koch Institute for Integrative Cancer Research at MIT
Format: Article
Published: Nature Publishing Group 2018
Online Access:http://hdl.handle.net/1721.1/116606
https://orcid.org/0000-0003-3675-6961
https://orcid.org/0000-0002-7045-7837
https://orcid.org/0000-0001-8031-0006
https://orcid.org/0000-0003-4617-8157
https://orcid.org/0000-0002-3393-6927
https://orcid.org/0000-0001-9076-8475
https://orcid.org/0000-0002-7577-4612
https://orcid.org/0000-0001-5785-8911
Description
Summary: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.

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