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 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 report that murine and human lung adenocarcinomas display hierarchical features with two distinct subpopulations, one with high Wnt signaling activity and another forming a niche that provides the Wnt ligand. The Wnt responder cells showed increased tumour propagation ability, suggesting that they have features of normal tissue stem cells. Genetic perturbation of Wnt production or signaling suppressed tumour progression. Small molecule inhibitors targeting essential post-translational modification of Wnt reduced tumour growth and dramatically decreased proliferative potential of the 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.