A WNT-Producing Niche Drives Lung Adenocarcinoma

Cells with stem-like properties have been described in tumors, but direct evidence of these cells in their niche in advanced solid tumors is limited. Secreted WNT signals are responsible for maintaining stem cells in various epithelial tissues, and WNT signaling is activated in lung adenocarcinoma. Tammela and colleagues showed that in a mouse model of mutant Kras–driven lung adenocarcinoma, tumor cells exhibited heterogeneity in their proliferative potential, and WNT signaling was required to sustain the proliferative potential. WNT is activated by palmitoylation by porcupine (encoded by Porcn), and the WNT pathway was activated in a subpopulation of lung adenocarcinoma cells near porcupine-positive cells that could provide the WNT signal. Further, inactivation of Porcn in the cancer cells prevented the shift from low-grade adenomas to adenocarcinomas, but tumors with a fraction of cells retaining Porcn could progress. Lgr5 is a WNT target gene involved in stem cell maintenance, and LGR5⁺ adenocarcinoma cells appeared in close proximity to porcupine⁺ cells and displayed persistent proliferative potential in mouse and human lung adenocarcinomas. The LGR5⁺ stem-like cells could give rise to porcupine⁺ cells, thereby creating their own niche. Similar to Porcn inactivation, combined inactivation of Lgr4 and Lgr5 reduced lung tumor burden and blocked the progression from adenomas to adenocarcinomas in mice. Treatment with a porcupine inhibitor suppressed tumor growth and extended survival in a mouse model of lung adenocarcinoma and suppressed the tumor-forming ability of transplanted cells, suggesting that WNT inhibition has potential as a therapeutic strategy to improve survival in lung adenocarcinoma by disrupting stem-like cells. Collectively, these results describe two subpopulations of lung adenocarcinoma cells, WNT responder cells with high WNT signaling activity and stem-like features, and cells that produce WNT ligand to provide a niche. WNT pathway inhibitors may disrupt the stem-like and niche cell phenotypes and provide potential benefit in patients with lung adenocarcinoma.

Tammela T, Sanchez-Rivera FJ, Cetinbas NM, Wu K, Joshi NS, Helenius K, et al. A Wnt-producing niche drives proliferative potential and progression in lung adenocarcinoma. Nature 2017;545:355–9.