An Exercise-Induced Metabolic Shield in Distant Organs Blocks Cancer Progression and Metastatic Dissemination

Danna Sheinboim, Shivang Parikh, Paulee Manich, Irit Markus, Sapir Dahan, Roma Parikh, Elisa Stubbs, Gali Cohen, Valentina Zemser-Werner, Rachel E. Bell, Sara Arciniegas Ruiz, Ruth Percik, Ronen Brenner, Stav Leibou, Hananya Vaknine, Gali Arad, Yariv Gerber, Lital Keinan-Boker, Tal Shimony, Lior BikovskiNir Goldstein, Keren Constantini, Sapir Labes, Shimonov Mordechai, Hila Doron, Ariel Lonescu, Tamar Ziv, Eran Nizri, Guy Choshen, Hagit Eldar-Finkelman, Yuval Tabach, Aharon Helman, Shamgar Ben-Eliyahu, Neta Erez, Eran Perlson, Tamar Geiger, Danny Ben-Zvi, Mehdi Khaled, Yftach Gepner, Carmit Levy

Research output: Contribution to journalArticlepeer-review

1 Scopus citations

Abstract

Exercise prevents cancer incidence and recurrence, yet the underlying mechanism behind this relationship remains mostly unknown. Here we report that exercise induces the metabolic reprogramming of internal organs that increases nutrient demand and protects against metastatic colonization by limiting nutrient availability to the tumor, generating an exercise-induced metabolic shield. Proteomic and ex vivo metabolic capacity analyses of murine internal organs revealed that exercise induces catabolic processes, glucose uptake, mitochondrial activity, and GLUT expression. Proteomic analysis of routinely active human subject plasma demonstrated increased carbohydrate utilization following exercise. Epidemiologic data from a 20-year prospective study of a large human cohort of initially cancer-free participants revealed that exercise prior to cancer initiation had a modest impact on cancer incidence in low metastatic stages but significantly reduced the likelihood of highly metastatic cancer. In three models of melanoma in mice, exercise prior to cancer injection significantly protected against metastases in distant organs. The protective effects of exercise were dependent on mTOR activity, and inhibition of the mTOR pathway with rapamycin treatment ex vivo reversed the exerciseinduced metabolic shield. Under limited glucose conditions, active stroma consumed significantly more glucose at the expense of the tumor. Collectively, these data suggest a clash between the metabolic plasticity of cancer and exercise-induced metabolic reprogramming of the stroma, raising an opportunity to block metastasis by challenging the metabolic needs of the tumor.

Original languageEnglish
Pages (from-to)4164-4178
Number of pages15
JournalCancer Research
Volume82
Issue number22
DOIs
StatePublished - 15 Nov 2022
Externally publishedYes

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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