Breast-cancer-secreted miR-122 reprograms glucose metabolism in premetastatic niche to promote metastasis
Miranda Y Fong, Weiying Zhou, Liang Liu, Aileen Y Alontaga, Manasa Chandra, Jonathan Ashby, Amy Chow, Sean Timothy Francis O'Connor, Shasha Li, Andrew R Chin, George Somlo, Melanie Palomares, Zhuo Li, Jacob R Tremblay, Akihiro Tsuyada, Guoqiang Sun, Michael A Reid, Xiwei Wu, Piotr Swiderski, Xiubao Ren, Yanhong Shi, Mei Kong, Wenwan Zhong, Yuan Chen, Shizhen Emily Wang, Miranda Y Fong, Weiying Zhou, Liang Liu, Aileen Y Alontaga, Manasa Chandra, Jonathan Ashby, Amy Chow, Sean Timothy Francis O'Connor, Shasha Li, Andrew R Chin, George Somlo, Melanie Palomares, Zhuo Li, Jacob R Tremblay, Akihiro Tsuyada, Guoqiang Sun, Michael A Reid, Xiwei Wu, Piotr Swiderski, Xiubao Ren, Yanhong Shi, Mei Kong, Wenwan Zhong, Yuan Chen, Shizhen Emily Wang
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 premetastatic 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 premetastatic 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. 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 premetastatic niche cells, cancer-derived extracellular miR-122 is able to reprogram systemic energy metabolism to facilitate disease progression.
Conflict of interest statement
The authors declare no conflict of interest.
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References
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