Cancer-cell-secreted exosomal miR-105 promotes tumour growth through the MYC-dependent metabolic reprogramming of stromal cells

• Published in: Nature cell biology Vol. 20; no. 5; pp. 597 - 609
• Main Authors: Yan, Wei, Wu, Xiwei, Zhou, Weiying, Fong, Miranda Y., Cao, Minghui, Liu, Juan, Liu, Xiaojing, Chen, Chih-Hong, Fadare, Oluwole, Pizzo, Donald P., Wu, Jiawen, Liu, Liang, Liu, Xuxiang, Chin, Andrew R., Ren, Xiubao, Chen, Yuan, Locasale, Jason W., Wang, Shizhen Emily
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 01.05.2018; Nature Publishing Group
• Subjects: 13/106; 13/51; 13/95; 38/109; 38/39; 38/89; 38/90; 38/91; 631/337/384/331; 631/67/2327; 631/67/327; 64/60; Ammonium; Animals; Biomedical and Life Sciences; Breast cancer; Breast Neoplasms - genetics; Breast Neoplasms - metabolism; Breast Neoplasms - pathology; Cancer; Cancer cells; Cancer Research; Cancer-Associated Fibroblasts - metabolism; Cancer-Associated Fibroblasts - pathology; Cell Biology; Cell Line, Tumor; Cell Proliferation; Cellular Reprogramming; Crosstalk; Developmental Biology; Displays (Marketing); Energy Metabolism; Environmental changes; Environmental effects; Exosomes - genetics; Exosomes - metabolism; Exosomes - pathology; Female; Fibroblasts; Gene Expression Regulation, Neoplastic; Genetic aspects; Glucose; Glucose metabolism; Glutamine; Humans; Lactic acid; Life Sciences; Metabolic wastes; Metabolism; Metabolites; Mice; Mice, Inbred NOD; Mice, SCID; MicroRNA; MicroRNAs - genetics; MicroRNAs - metabolism; miRNA; Myc protein; NIH 3T3 Cells; Nutrients; Paracrine Communication; Proto-Oncogene Proteins c-myc - genetics; Proto-Oncogene Proteins c-myc - metabolism; Signal Transduction; Stem Cells; Stromal cells; Stromal Cells - metabolism; Stromal Cells - pathology; Time Factors; Tumor Burden; Tumor Cells, Cultured; Tumor Microenvironment; Tumors
• ISSN: 1465-7392; 1476-4679
• DOI: 10.1038/s41556-018-0083-6

Cancer and other cells residing in the same niche engage various modes of interactions to synchronize and buffer the negative effects of environmental changes. Extracellular microRNAs (miRNAs) have recently been implicated in the intercellular crosstalk. Here we show a mechanistic model involving breast-cancer-secreted, extracellular-vesicle-encapsulated miR-105, which is induced by the oncoprotein MYC in cancer cells and, in turn, activates MYC signalling in cancer-associated fibroblasts (CAFs) to induce a metabolic program. This results in the capacity of CAFs to display different metabolic features in response to changes in the metabolic environment. When nutrients are sufficient, miR-105-reprogrammed CAFs enhance glucose and glutamine metabolism to fuel adjacent cancer cells. When nutrient levels are low and metabolic by-products accumulate, these CAFs detoxify metabolic wastes, including lactic acid and ammonium, by converting them into energy-rich metabolites. Thus, the miR-105-mediated metabolic reprogramming of stromal cells contributes to sustained tumour growth by conditioning the shared metabolic environment. Consistent crosstalk between cancer cells and stromal cells exists in the tumour microenvironment. Yan et al. show that exosomal miR-105 derived from cancer cells confers metabolic plasticity in recipient cancer-associated fibroblasts to adapt to nutrient-replete and -deplete conditions, thereby sustaining tumour growth.