OPN released from p62-deficient adipocytes enhances fatty-acid oxidation in tumor cells.

  • Major finding: OPN released from p62-deficient adipocytes enhances fatty-acid oxidation in tumor cells.

  • Concept: p62 loss promotes an OPN-mediated increase in tumor cell invasion, migration, and metastasis.

  • Impact: An adipocyte–tumor cell cross-talk may increase tumor nutrient availability to drive aggressive disease.

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Obesity has been linked to an increased risk of cancer, including prostate cancer, but the cross-talk between adipocytes and tumor cells remains poorly understood. To better understand adipocyte–tumor cross-talk, Huang and colleagues used the TRAMP+ mouse model of prostate cancer and selectively inactivated the signaling adaptor and autophagy substrate p62 in adipocytes (p62Adipo), which results in increased adiposity. These TRAMP+/p62Adipo mice exhibited increased adiposity and more aggressive prostate cancer than TRAMP+ mice with increased tumor cell proliferation and metastasis. However, the increase in adiposity induced by p62 depletion was lessened by the presence of prostate tumors. p62 deficiency resulted in reduced mTORC1 activity in the adipose tissue, thereby preventing the activation of energy-consuming pathways in the adipose tissue and saving nutrients to feed the tumor. Accordingly, p62 deficiency in adipocytes enhanced fatty-acid oxidation in tumor cells, with upregulation of genes involved in fatty-acid oxidation including carnitine palmitoyltransferase 1A (CPT1A). Mechanistically, p62 loss produced an inflammatory response in the adipose tissue and increased osteopontin (OPN) secretion from adipocytes. OPN increased tumor cell CPT1A expression to promote fatty-acid oxidation and drive tumor cell proliferation and invasion. Analysis of data from The Cancer Genome Atlas revealed that, in patients with castration-resistant prostate cancer, high expression of SPP1 (encoding osteopontin), CPT1A, and ACAD9 (another fatty-acid oxidation gene) was associated with poorer outcomes. Collectively, these findings reveal a mechanism by which p62 deficiency in adipocytes can enhance fatty-acid oxidation in tumor cells to promote an aggressive prostate cancer phenotype, and these data may provide insight into the link between cancer and obesity.

Huang J, Duran A, Reina-Campos M, Valencia T, Castilla EA, Müller TD, et al. Adipocyte p62/SQSTM1 suppresses tumorigenesis through opposite regulations of metabolism in adipose tissue and tumor. Cancer Cell 2018;33:770–84.

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