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Suppression of MAPK signaling in BRAF ‐activated PTEN ‐deficient melanoma by blocking β‐catenin signaling in cancer‐associated fibroblasts
Author(s) -
Zhou Linli,
Yang Kun,
Dunaway Spencer,
AbdelMalek Zalfa,
Andl Thomas,
Kadekaro Ana Luisa,
Zhang Yuhang
Publication year - 2018
Publication title -
pigment cell and melanoma research
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.618
H-Index - 105
eISSN - 1755-148X
pISSN - 1755-1471
DOI - 10.1111/pcmr.12657
Subject(s) - pten , cancer research , melanoma , mapk/erk pathway , tumor microenvironment , stromal cell , signal transduction , catenin , protein kinase b , chemistry , microbiology and biotechnology , biology , wnt signaling pathway , pi3k/akt/mtor pathway , tumor cells
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.