Clonal Heterogeneity Supports Mitochondrial Metabolism in Pancreatic Cancer

The pancreatic tumor microenvironment is a complex ecosystem, with numerous cell types functioning to create a niche supporting cancer cell proliferation. Recent efforts are identifying subpopulations among each of these cell types, including diversity among the behavior of cancer cells. In this study, we identify two distinct metabolic subclasses within a single pancreatic tumor cell population capable of metabolic crosstalk. Examining the exchanged metabolites, we find an unexpected role for asparagine in supporting proliferation during mitochondrial inhibition. Furthermore, we find that depletion of extracellular asparagine sensitizes pancreatic tumors to mitochondrial inhibition by phenformin, which could provide a powerful new strategy for this difficult to treat disease.