Suppression of MAPK signaling in BRAF ‐activated PTEN ‐deficient melanoma by blocking β‐catenin signaling in cancer‐associated fibroblasts

Summary Cancer‐associated fibroblasts ( CAF s) in the tumor microenvironment have been associated with formation of a dynamic and optimized niche for tumor cells to grow and evade cell death induced by therapeutic agents. We recently reported that ablation of β‐catenin expression in stromal fibroblasts and CAF s disrupted their biological activities in in vitro studies and in an in vivo B16F10 mouse melanoma model. Here, we show that the development of a BRAF ‐activated PTEN ‐deficient mouse melanoma was significantly suppressed in vivo after blocking β‐catenin signaling in CAF s. Further analysis revealed that expression of phospho‐Erk1/2 and phospho‐Akt was greatly reduced, effectively abrogating the activating effects and abnormal cell cycle progression induced by Braf and Pten mutations. In addition, the epithelial–mesenchymal transition ( EMT )‐like process was also suppressed in melanoma cells. Taken together, our data highlight an important crosstalk between CAF s and the RAF ‐ MEK ‐ ERK signaling cascade in BRAF ‐activated melanoma and may offer a new approach to abrogate host‐dependent drug resistance in targeted therapy.