Abstract
p62 deficiency in the tumor microenvironment induces inflammation and prostate tumor progression.
Major finding: p62 deficiency in the tumor microenvironment induces inflammation and prostate tumor progression.
Mechanism: Stromal p62 loss promotes IL6/TGFβ production via mTORC1–c-MYC repression and metabolic deregulation.
Impact: Inhibition of metabolic reprogramming in stromal cells may limit inflammation and tumor progression.
Recent data has shown an increasingly important role for the tumor microenvironment in the progression of many types of cancer, including prostate cancer, but the mechanisms by which the tumor stroma influences epithelial tumor cells remain poorly understood. The scaffold protein p62 (also known as sequestosome 1) is overexpressed in several epithelial tumors and has been implicated in mTOR-regulated metabolic signaling; however, its role in stromal cells is unknown. Valencia and colleagues found that p62 protein levels were downregulated in stromal cells of primary human prostate tumors, and that decreased p62 expression was correlated with progression to aggressive tumors. Deletion of p62 allowed for enhanced tumor growth and induced an activated, cancer associated fibroblast–like phenotype in the tumor stroma, characterized by upregulation of TGFβ and inflammatory cytokines, in particular IL6, which was necessary for the increased tumor growth in p62-deficient mice. Decreased glucose and amino acid metabolism in p62-deficient fibroblasts resulted in increased reactive oxygen species accumulation, which was required for IL6 production. This metabolic deregulation was mediated by inhibition of mTOR complex 1 (mTORC1) and subsequent repression of c-MYC in stromal fibroblasts in the absence of p62; knockdown of c-MYC in wild-type fibroblasts led to elevated IL6 production and enhanced prostate cancer proliferation and invasion, similar to the p62-deficient phenotype, suggesting that p62-dependent regulation of c-MYC in tumor stroma is necessary for its tumor-suppressive function. Importantly, inactivation of the p62–mTORC1–c-MYC pathway was also found to be clinically relevant, as decreased expression of p62 was correlated with a reduction in c-MYC levels and mTORC1 activity in human prostate and breast cancer stroma. These results demonstrate a critical role for stromal p62 as a tumor suppressor and support targeted inhibition of the tumor microenvironment as a therapeutic approach to limit tumor progression.
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