Breast-cancer-secreted miR-122 reprograms glucose metabolism in premetastatic niche to promote metastasis

Abstract

Reprogrammed glucose metabolism as a result of increased glycolysis and glucose uptake is a hallmark of cancer. Here we show that cancer cells can suppress glucose uptake by non-tumour cells in the pre-metastatic niche, by secreting vesicles that carry high levels of the miR-122 microRNA. High miR-122 levels in the circulation have been associated with metastasis in breast cancer patients and we show that cancer-cell-secreted miR-122 facilitates metastasis by increasing nutrient availability in the pre-metastatic niche. Mechanistically cancer-cell-derived miR-122 suppresses glucose uptake by niche cells in vitro and in vivo by downregulating the glycolytic enzyme pyruvate kinase (PKM). In vivo inhibition of miR-122 restores glucose uptake in distant organs, including brain and lungs, and decreases the incidence of metastasis. These results demonstrate that by modifying glucose utilization by recipient pre-metastatic niche cells, cancer-derived extracellular miR-122 is able to reprogram systemic energy metabolism to facilitate disease progression.

Cross-kingdom inhibition of breast cancer growth by plant miR159

“…ISH and IHC were performed as previously described [17]. The miR159 detection probes were obtained from Exiqon (Woburn, MA).…”

“…miRNAs can be secreted through extracellular vesicles (EVs), such as exosomes, shedding vesicles, and apoptotic bodies, or in complexes with protein or lipid-based carriers [9,10]. Accumulating evidence demonstrates that miRNAs can be transferred via EVs to neighboring or distant cells to modulate cell function [11][12][13][14][15][16][17][18][19]. Extracellular miRNAs are therefore emerging as a new group of messengers and effectors in intercellular communication.…”

Linear-array-based photoacoustic tomography for label-free high-throughput detection and quantification of circulating melanoma tumor cell clusters

“…LA-PAT has been demonstrated to detect and quantify CTC clusters. In addition, photoacoustic imaging can measure other important biological parameters, including tumor depth, the oxygen saturation of hemoglobin, metabolic rate, and tumor stiffness [26][27][28][29] , all of which are closely related to metastasis [30][31][32] . With the capability to detect and quantify CTC clusters and the potential to provide multidimensional information on tumor metastasis, LA-PAT is a promising tool for both preclinical cancer metastasis study and clinical tumor therapy.…”

The Role of micro RNAs in Breast Cancer Metastasis: Preclinical Validation and Potential Therapeutic Targets

“…miR-122: miR-122 has been identified as a miR with the capability to reprogram glucose metabolism in the premetastatic niche to promote metastasis (85). miR-122 is secreted in vesicles by BC cells and down-regulates the glycolytic enzyme pyruvate kinase M (PKM) to suppress glucose uptake by stromal cells of the metastatic niche and cells located in distant organs (86)(87)(88).…”

“…miR-122 is secreted in vesicles by BC cells and down-regulates the glycolytic enzyme pyruvate kinase M (PKM) to suppress glucose uptake by stromal cells of the metastatic niche and cells located in distant organs (86)(87)(88). Metastatic colonization in brain and lungs was observed after intracardiac injection of MDA-MB-231 cells into mice pretreated with endocytic vesicles containing miR-122, whereas no metastases were detected in controls (85). From a clinical point of view, it has been noted that miR-122 levels in the circulation correlate with metastatic progression in BC patients (89).…”