MicroRNA-Mediated Metabolic Shaping of the Tumor Microenvironment

SIMPLE SUMMARY: Ongoing studies demonstrate the importance of metabolism in cancer development and progression. Metabolic alterations occur, not only in cancer cells, but also in the tumor microenvironment (TME). The continuous crosstalk between tumor cells and stromal and immune cells deeply affects metabolic rewiring. miRs, small noncoding RNAs involved in post-transcriptional regulation, are important mediators in these processes. In-depth knowledge of these interactions is crucial in understanding cancer progression and, consequently, for the development of new therapies. ABSTRACT: The metabolism of cancer cells is generally very different from what is found in normal counterparts. However, in a tumor mass, the continuous crosstalk and competition for nutrients and oxygen among different cells lead to metabolic alterations, not only in cancer cells, but also in the different stromal and immune cells of the tumor microenvironment (TME), which are highly relevant for tumor progression. MicroRNAs (miRs) are small non-coding RNAs that silence their mRNA targets post-transcriptionally and are involved in numerous physiological cell functions as well as in the adaptation to stress situations. Importantly, miRs can also be released via extracellular vesicles (EVs) and, consequently, take part in the bidirectional communication between tumor and surrounding cells under stress conditions. Certain miRs are abundantly expressed in stromal and immune cells where they can regulate various metabolic pathways by directly suppressing enzymes or transporters as well as by controlling important regulators (such as transcription factors) of metabolic processes. In this review, we discuss how miRs can induce metabolic reprogramming in stromal (fibroblasts and adipocytes) and immune (macrophages and T cells) cells and, in turn, how the biology of the different cells present in the TME is able to change. Finally, we debate the rebound of miR-dependent metabolic alterations on tumor progression and their implications for cancer management.