Sapp, K. M. | bioRxiv Science

bioRxiv2020

Dissecting cell type-specific metabolism in pancreatic ductal adenocarcinoma

Tumors are composed of many different cell types including cancer cells, fibroblasts, and immune cells. Dissecting functional metabolic differences between various cell types within a mixed population can be limited by the rapid turnover of metabolites relative to the time needed to isolate cells. To overcome this challenge, we traced isotope-labeled nutrients into macromolecules that turn over more slowly than metabolites. This approach was used to assess differences between cancer cell and fibroblast metabolism in pancreatic cancer organoid-fibroblast co-cultures and in pancreatic tumors. In these contexts, we find pancreatic cancer cells exhibit increased pyruvate carboxylation relative to fibroblasts, and that this flux depends on both pyruvate carboxylase and malic enzyme 1 activity. Consequently, expression of both enzymes in cancer cells is necessary for organoid and tumor growth, demonstrating that dissecting the metabolism of specific cell populations within heterogeneous systems can identify dependencies that may not be evident from studying isolated cells in culture or bulk tumor tissue.

cancer biology↗

bioRxiv2020

Caloric restriction alters lipid metabolism to contribute to tumor growth inhibition

Dietary interventions can change metabolite levels in the tumor microenvironment, which may then affect cancer cell metabolism to alter tumor growth1-6. Although caloric restriction (CR) and the ketogenic diet (KD) are often thought to inhibit tumor growth through lowering blood glucose and insulin levels7-12, only CR inhibits the growth of pancreatic ductal adenocarcinoma allografts in mice, demonstrating that this diet can limit tumor growth in other ways. A change in nutrient availability observed with CR, but not the KD, that can contribute to tumor growth inhibition is lower lipid levels in the plasma and in tumor interstitial fluid. Limiting exogenous lipid availability to cultured cancer cells results in up-regulation of stearoyl-CoA desaturase (SCD), an enzyme that converts saturated fatty acids to monounsaturated fatty acids. Fatty acid desaturation is required to dispose of toxic saturated fatty acids, and not because monounsaturated fatty acids are specifically needed for proliferation. Surprisingly, CR also inhibits tumor SCD activity, and enforced SCD expression confers resistance to the effects of CR. Therefore, CR both limits lipid availability and impairs tumor SCD activity, thereby limiting cancer cell adaptation to a diet-induced change in the tumor microenvironment that results in tumor growth inhibition.

cancer biology↗