BRAF Inhibitors Reprogram Cancer-Associated Fibroblasts to Drive Matrix Remodeling and Therapeutic Escape in Melanoma

The tumor stroma and its cellular components are known to play an important role in tumor response to treatment. Here, we report a novel resistance mechanism in melanoma that is elicited by BRAF inhibitor (BRAFi)-induced noncanonical activation of nuclear β-catenin signaling in cancer-associated fib...

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Bibliographic Details
Published in:Cancer research (Chicago, Ill.) Ill.), 2022-02, Vol.82 (3), p.419-432
Main Authors: Liu, Tianyi, Zhou, Linli, Xiao, Yao, Andl, Thomas, Zhang, Yuhang
Format: Article
Language:English
Subjects:
Animals
Cancer-Associated Fibroblasts - metabolism
Cell Line, Tumor
Humans
Melanoma - genetics
Mice
Proto-Oncogene Proteins B-raf - antagonists & inhibitors
Xenograft Model Antitumor Assays - methods
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Summary:The tumor stroma and its cellular components are known to play an important role in tumor response to treatment. Here, we report a novel resistance mechanism in melanoma that is elicited by BRAF inhibitor (BRAFi)-induced noncanonical activation of nuclear β-catenin signaling in cancer-associated fibroblasts (CAF). Treatment with BRAFi leads to an expanded CAF population with increased β-catenin nuclear accumulation and enhanced biological properties. This CAF subpopulation is essential for melanoma cells to proliferate and acquire resistance to BRAFi/MEK inhibitors (MEKi). Mechanistically, BRAFi induces BRAF-CRAF heterodimerization and subsequent activation of ERK signaling in CAFs, leading to inactivation of the β-catenin destruction complex. RNA-seq identified periostin (POSTN) as a major downstream effector of β-catenin in CAFs. POSTN compensates for the loss of β-catenin in CAFs and mediates melanoma cell BRAFi/MEKi resistance. In melanoma cells, POSTN activates phosphoinositide 3-kinase (PI3K)/AKT signaling and subsequently reactivates the ERK pathway that was inhibited by BRAFi/MEKi. Collectively, these data underscore the role of BRAFi-induced CAF reprogramming in matrix remodeling and therapeutic escape of melanoma cells. SIGNIFICANCE: β-Catenin activation in cancer-associated fibroblasts in response to BRAF inhibitors stimulates POSTN secretion to promote resistance in cancer cells, revealing POSTN as a potential matrix target in cancer therapy.
ISSN:0008-5472
1538-7445
DOI:10.1158/0008-5472.CAN-21-0614