期刊
PIGMENT CELL & MELANOMA RESEARCH
卷 31, 期 2, 页码 -出版社
WILEY
DOI: 10.1111/pcmr.12657
关键词
beta-catenin; BRAF; Cancer-associated fibroblasts; Melanoma; Microenvironment
资金
- Harry J. Lloyd Charitable Trust
- Melanoma Research Alliance [300586]
- Elsa U. Pardee Foundation
- Cincinnati Cancer Center
- Skin Cancer Foundation
Cancer-associated fibroblasts (CAFs) 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 beta-catenin expression in stromal fibroblasts and CAFs 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 beta-catenin signaling in CAFs. 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 CAFs 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.
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