Journal Article

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

Tammela, Tuomas, Jacks, Tyler, Park, Yoona, Gu, Xin, Schmidt, Leah, Katajisto, Pekka, Cetinbas, Naniye Malli, Cornwall-Brady, Milton, Bhutkar, Arjun, Xue, Wen, Helenius, Katja, Kerper, Natanya R., Wu, Katherine, Azimi, Roxana, Wesselhoeft, R. Alexander, Yilmaz, Ömer H., Joshi, Nikhil S., Sanchez-Rivera, Francisco J.

2017

Overview

A subset of Kras and p53 mutant cancer cells acts as a Wnt-producing niche for another cancer cell subset, and porcupine inhibition disrupts Wnt secretion in this niche, thereby suppressing proliferative potential and leading to therapeutic benefit. Lung cancer niche drives tumour growth Lung adenocarcinomas are aggressive tumours which are associated with poor treatment outcome. Tyler Jacks and colleagues now show that lung adenocarcinomas display two distinct subpopulations of tumour cells. One of these shows high levels of Wnt signalling and gives rise to the second one that produces Wnt ligands. The latter population fuels tumour growth of the former, showing that lung cancer cells can produce their own niche. These findings shed new light on the mechanisms underlying intratumoural heterogeneity which may have therapeutic implications. 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 , 4 , 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.

• Publisher: Nature Publishing Group UK,Nature Publishing Group
• Subject: 13 / 13/106 / 13/31 / 13/89 / 38 / 38/109 / 38/77 / 42 / 42/44 / 631/67/1059/602 / 631/67/1612/1350 / 631/67/2329 / 631/67/71 / Adenocarcinoma / Adenocarcinoma - metabolism / Adenocarcinoma - pathology / Adenocarcinoma of Lung / Animals / Anticancer properties / Cancer cells / Cancer metastasis / Cancer research / Cell Proliferation - drug effects / Disease Progression / Drug resistance / Female / Gene expression / Growth factors / Heterogeneity / Histology / Humanities and Social Sciences / Humans / letter / Ligands / Lung cancer / Lung diseases / Lung Neoplasms - metabolism / Lung Neoplasms - pathology / Male / Medical research / Mice / multidisciplinary / Neoplasm Transplantation / Neoplastic Stem Cells - metabolism / Neoplastic Stem Cells - pathology / Perturbation / Phenotypes / Protein Processing, Post-Translational - drug effects / Science / Signal transduction / Signaling / Small Molecule Libraries - pharmacology / Stem Cell Niche / Stem cell transplantation / Stem cells / Subpopulations / Survival Rate / Tumors / Wnt protein / Wnt Proteins - biosynthesis / Wnt Proteins - chemistry / Wnt Proteins - metabolism / Wnt Signaling Pathway