Microenvironmental regulation of cancer cell metabolism: implications for experimental design and translational studies

Abstract

Cancers have an altered metabolism, and there is interest in understanding precisely how oncogenic transformation alters cellular metabolism and how these metabolic alterations can translate into therapeutic opportunities. Researchers are developing increasingly powerful experimental techniques to study cellular metabolism, and these techniques have allowed for the analysis of cancer cell metabolism, both in tumors and in ex vivo cancer models. These analyses show that, while factors intrinsic to cancer cells such as oncogenic mutations, alter cellular metabolism, cell-extrinsic microenvironmental factors also substantially contribute to the metabolic phenotype of cancer cells. These findings highlight that microenvironmental factors within the tumor, such as nutrient availability, physical properties of the extracellular matrix, and interactions with stromal cells, can influence the metabolic phenotype of cancer cells and might ultimately dictate the response to metabolically targeted therapies. In an effort to better understand and target cancer metabolism, this Review focuses on the experimental evidence that microenvironmental factors regulate tumor metabolism, and on the implications of these findings for choosing appropriate model systems and experimental approaches.

Keywords: Cancer; Cancer models; Metabolism; Microenvironment; Nutrient availability; Nutrient sensing.

Fig. 1.

Advantages and disadvantages of cancer model systems to study metabolism. Cancer models vary in complexity from 2D monolayer cultures to in vivo systems. The most experimentally tractable cancer models are amenable to many different approaches to study metabolism, but fail to replicate the complex conditions found in a tumor. On the other hand, more physiologically complex cancer model systems, such as mouse models, are less tractable and complicate the interpretation of many metabolic assays. Models such as ex vivo cultures of cancer cells in 3D models like organoids or spheroids, or ex vivo cultures of tumor slices, lay on this continuum between tractability and physiological relevance. Each of these models presents with its own set of advantages and pitfalls that researchers need to consider when designing cancer metabolism experiments. ECM, extracellular matrix.

Fig. 2.

The cancer model system chosen can affect metabolic phenotypes. When the same cells are studied in different cancer model systems, the main carbon source that feeds the TCA cycle changes. For example, when cancer cells are implanted to form tumors in mice, an increase in the contribution of glucose-derived carbon to the TCA cycle, together with a reduced contribution of glutamine carbon, is observed, even though the same cells predominantly rely on glutamine in less physiological in vitro culture systems. a-KG, alpha-ketoglutarate; OAA, oxaloacetate; TCA, tricarboxylic acid.