Obesity is a risk factor for cancer; however, the molecular mechanisms linking them are poorly understood. Now, new research by Jorge Moscat, Maria T. Diaz-Meco and colleagues shows that p62 (also known as sequestosome 1; SQSTM1) is a ‘metabolic’ tumour suppressor in a genetically induced obese mouse model of prostate cancer. The selective loss of p62 from adipose tissue resulted in a more aggressive tumour phenotype by promoting osteopontin-driven fatty acid oxidation and inhibition of tumour-induced nutrient wasting.

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Mouse studies investigating the link between obesity and cancer typically induce obesity by feeding high-fat diets or inactivating the leptin pathway. “Both of these strategies lead to increased calorie intake or hormonal pleiotropic disarrangements, which preclude molecular and cellular studies of the crosstalk between adipocytes and tumour cells,” explains Moscat. To avoid these problems, the researchers crossed an adipose tissue-specific knockout of p62, which develops obesity without the need of a high-fat diet, with a mouse model of prostate cancer. This novel model provided the ideal background to study the link between obesity and cancer.

The researchers showed that inactivation of p62 in adipocytes results in a more aggressive and invasive tumour phenotype compared with those from mice with active p62. Loss of p62 in adipocytes from the prostate cancer model increased the systemic production and secretion of osteopontin (a cytokine implicated in advancing tumour aggressiveness) and promoted fatty acid oxidation in tumour cells. This effect is important, as fatty acid oxidation is the main bioenergetic pathway for non-glycolytic tumours, such as prostate cancer. “Increased fatty acid oxidation makes the tumour more invasive because it provides the energy necessary for cancer cells to undergo epithelial–mesenchymal transition to metastasize,” adds Diaz-Meco.

Loss of p62 in adipocytes from the prostate cancer model increased the systemic production and secretion of osteopontin

In Moscat and Diaz-Meco’s mouse model, p62 inactivation also prevented tumour-driven energy ‘wasting’ in adipocytes. Under normal physiological conditions, tumour cells trigger a process in adipocytes termed fat cachexia, in which adipocytes metabolize fatty acids without producing energy. Therefore, during fat cachexia, tumour cells continue to metabolize nutrients, but at the detriment of their energy reserves. The inactivation of p62 in adipocytes, however, prevented this process and therefore increased nutrient availability for tumour cells.

“A critical question that needs to be addressed is how p62 controls the synthesis of osteopontin,” concludes Diaz-Meco. “This is important because if we can find a way to inhibit osteopontin synthesis, we will curtail the ability of the tumour to increase fatty acid oxidation, which will lead to its ‘starvation’ and likely reduce its metastatic potential.”