p62-Induced Cancer-Associated Fibroblast Activation via the Nrf2-ATF6 Pathway Promotes Lung Tumorigenesis

SIMPLE SUMMARY: Cancer-associated fibroblasts (CAF) arise from normal fibroblasts within the tumor microenvironment (TME) and promote tumorigenesis through metabolic reprograming and secretion of tumor promoting molecules such as transforming growth factor beta (TGFβ). Here, we show that autophagy plays a key role in CAF activation. During CAF activation, fibroblasts induce the mRNA expression of p62, and resulting p62 targets Keap1 for lysosomal degradation, which allows the nuclear translocation of Nrf2 and transcriptional induction of antioxidant responses. The transcriptional targets of Nrf2 include ATF6, which mediates ER stress responses. Taken together, normal fibroblasts are differentiated into CAFs as protective responses to stresses under TME via the p62-Nrf2 pathway. ABSTRACT: Cancer-associated fibroblasts (CAFs) are important in tumor progression. The autophagy adaptor protein, p62/SQSTM1/Sequestosome-1, is up-regulated in tumors, but down-regulated in CAFs in the early stages of lung adenocarcinoma. We investigated whether p62-induced autophagy might control CAF activation. Under CAF-inducing conditions, like hypoxia or cancer cell co-cultures, p62 ablation or autophagy inhibition with hydroxychloroquine (HCQ) impaired CAF activation and reduced transforming growth factor beta (TGFβ) production, which impeded tumor growth. During CAF activation, p62-induced autophagy up-regulated the expression of the anti-oxidant signaling protein, nuclear factor erythroid 2-related factor 2 (Nrf2), and the ER-stress response regulator, activating transcription factor 6 (ATF6). Genetically or pharmacologically inhibiting the Nrf2-ATF6 pathway totally blocked CAF activation and tumor progression. These results demonstrate that p62 is a key modulator of primary lung adenocarcinoma progression. Thus, targeting the p62-Nrf2 autophagy signaling pathway might be a novel, stroma-focused, cancer prevention and/or treatment strategy.