The considerable variability within tissue microenvironments as well as the multiclonality of cancers leads to heterogeneity within tumors, increasing the probablility of cellular states that promote resistance to therapy and eventually lead to reconstitution of the tumor by treatment-resistant cancer cells, which in some case have properties of normal tissue stem cells. Wnt signals are important in the maintenance of stem cells in various epithelial tissues, including in lung development and regeneration. We hypothesized that Wnt signals would also contribute to hierarchial organization of KrasG12D and KrasG12D; tp53Δ/Δ mouse lung adenocarcinomas. Indeed, rare cells with nuclear βeta-catenin were detected in mouse tumors in vivo. Stimulating KP mouse lung adenocarcinoma cells with recombinant Wnt3a promoted their spheroid-forming ability in a 3-dimensional Matrigel culture system, whereas RNAi or small-molecule inhibitors targeting Porcupine, an enzyme required for post-translational palmitoylation of Wnt, suppressed tumor initiation in vitro and in vivo. Interestingly, either the stimulation or inhibition of the Wnt signaling pathway had no effect on growth of KP lung cancer cells in standard 2-dimensional cell culture, suggesting that Wnt signaling qualitatively modulates the cellular phenotype instead of controlling cell proliferation. We propose that targeting the Wnt signaling pathway can stimulate re-differentiation of lung adenocarcinoma cells, which may render them more sensitive to conventional anti-tumor therapies.

Citation Format: Tuomas Tammela, Natanya Kerper, Wen Xue, Nikhil Joshi, Pekka Katajisto, Tyler Jacks. Wnt signaling promotes tumor propagation in a mouse model of lung adenocarcinoma. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 99. doi:10.1158/1538-7445.AM2014-99