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      Megakaryocytes Mediate Hyperglycemia-Induced Tumor Metastasis.

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          High blood glucose has long been established as a risk factor for tumor metastasis, yet the molecular mechanisms underlying this association have not been elucidated. Here we describe that hyperglycemia promotes tumor metastasis via increased platelet activity. Administration of glucose, but not fructose, reprogrammed the metabolism of megakaryocytes to indirectly prime platelets into a prometastatic phenotype with increased adherence to tumor cells. In megakaryocytes, a glucose metabolism-related gene array identified the mitochondrial molecular chaperone glucose-regulated protein 75 (GRP75) as a trigger for platelet activation and aggregation by stimulating the Ca2+-PKCα pathway. Genetic depletion of Glut1 in megakaryocytes blocked MYC-induced GRP75 expression. Pharmacologic blockade of platelet GRP75 compromised tumor-induced platelet activation and reduced metastasis. Moreover, in a pilot clinical study, drinking a 5% glucose solution elevated platelet GRP75 expression and activated platelets in healthy volunteers. Platelets from these volunteers promoted tumor metastasis in a platelet-adoptive transfer mouse model. Together, under hyperglycemic conditions, MYC-induced upregulation of GRP75 in megakaryocytes increases platelet activation via the Ca2+-PKCα pathway to promote cancer metastasis, providing a potential new therapeutic target for preventing metastasis. SIGNIFICANCE: This study provides mechanistic insights into a glucose-megakaryocyte-platelet axis that promotes metastasis and proposes an antimetastatic therapeutic approach by targeting the mitochondrial protein GRP75.

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          Author and article information

          Cancer Res
          Cancer research
          American Association for Cancer Research (AACR)
          November 01 2021
          : 81
          : 21
          [1 ] Department of Cellular and Genetic Medicine, School of Basic Medical Sciences, Fudan University, Shanghai, China.
          [2 ] Department of Oral Implantology, School and Hospital of Stomatology, Tongji University; Shanghai Engineering Research Center of Tooth Restoration and Regeneration, Shanghai, China.
          [3 ] Phase I Clinical Center, Shandong Cancer Hospital and Institute, Shandong First Medical University and Shandong Academy of Medical Science, Jinan, China.
          [4 ] Department of Medical Oncology, Shuguang Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai, China.
          [5 ] Department of Reproductive Medicine, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi, China.
          [6 ] Department of Cardiology, Huashan Hospital Affiliated to Fudan University, Shanghai 200040, China.
          [7 ] Department of Medicine, Health and Caring Science, Division of Diagnostics and Specialist Medicine, Unit of Cardiovascular Medicine, Linköping University, Linköping, Sweden.
          [8 ] Shenzhen Eye Hospital, Shenzhen Key Laboratory of Ophthalmology, Affiliated Shenzhen Eye Hospital of Jinan University, Shenzhen, China.
          [9 ] Medical Oncology Department of Jinling Hospital, Medical School of Nanjing University, Nanjing, China.
          [10 ] Department of Cellular and Genetic Medicine, School of Basic Medical Sciences, Fudan University, Shanghai, China. yunlongyang@fudan.edu.cn liuwen@shmu.edu.cn.
          ©2021 American Association for Cancer Research.


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