Tumor Microenvironment Influences Metabolism of Cancer Cells

When we think about tumor heterogeneity, we often imagine variation that originates from genetic and/or epigenetic mechanisms. However, there is increasing evidence that variation exists at the level of cellular metabolism and that this intratumoral heterogeneity could be important to tumor progression. The vast majority of RAS-driven tumors are notoriously aggressive and do not respond to chemotherapies, and it is conceivable that the metabolic heterogeneity found within these tumors could be contributing to their aggressiveness or to chemoresistance. Variations in metabolic wiring could allow some cancers cells within the tumor to be better positioned to survive specific stresses within the harsh tumor microenvironment. Moreover, metabolic adaptation to these stresses might also impact signaling pathways that regulate macropinocytosis and autophagy, both critical routes of nutrient supply in RAS-driven tumors^{1, 2}.

In rapidly proliferating RAS-mutated pancreatic cancer cells, cellular metabolism comes in at least two broad flavors – cells that are glycolytic and those that are lipogenic³. Interestingly, the glycolytic cells, which have elevated levels of various components of glycolysis, are associated with more mesenchymal properties, while lipogenic cells that are enriched for various lipid metabolites are associated with a classical, more epithelial cell type^{3, 4}. This is a great example of how metabolic heterogeneity within RAS-driven tumors might be contributing to tumor aggressiveness and/or invasion. In my lab we have observed that in addition to the differential usage of various metabolic pathways, RAS-mutated pancreatic cancers also exhibit intratumoral variation in how they obtain nutrients, with some cells depending on nutrient transporters and other cells relying on protein scavenging pathways, such as macropinocytosis. Altogether, it looks like it will be imperative to take into account this heterogeneity when designing novel therapeutic strategies for this disease.

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