Obesity has been associated with increased incidence and mortality of a wide variety of human cancers including colorectal cancer. However, the molecular mechanism underlying the functional interaction between obesity and cancer remains elusive. Here, we demonstrated that adipocytes isolated from adipose tissues of colon cancer patients play an important role in promoting tumor cell survival and progression by altering cellular metabolism. In stage IV colon cancer cases, abundant adipocytes were found in close association with invasive colon cancer cells. Co-culture of adipocytes with colon cancer cells led to direct transfer of free fatty acids (FAs) released by the adipocytes to colon cancer cells. Uptake of FAs allowed the cancer cells to survive nutrient deprivation conditions by upregulating mitochondrial fatty acid β-oxidation, suggesting that FAs from adipocytes were used as an energy source by the cancer cells. In addition, we found that co-culture of adipocytes or treating cells with fatty acids induced autophagy in colon cancer cells as a result of AMPK activation. Inhibition of autophagy attenuated the ability of cancer cells to utilize FAs and blocked the growth promoting effect of adipocytes. Furthermore, we found that adipocytes induced dedifferentiation of tumor cells in primary colon cancer cells and mouse tumor organoids. Taken together, these results identify adipocytes as active contributors to the tumor microenvironment that promote tumor growth and survival by serving as an energy provider and a metabolic regulator for the embedded colon cancer cells.

Citation Format: Yang-an Wen, Xiaopeng Xiong, Jennifer Harris, Yekaterina Zaytseva1, Tianyan Gao. Adipocytes-mediated autophagy activation and metabolic reprogramming promotes colon cancer survival. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 4088.