Dataset Information

Exercise forms a metabolic-shield in distant organs blocking cancer progression and metastatic dissemination-Part 2

ABSTRACT: Exercise prevents cancer incidence and recurrence, yet the underlying mechanism remains mostly unknown. Here we report that exercise induces a metabolic reprogramming of internal organs, increasing their nutrient demand, thus protecting them against metastatic colonization by limiting nutrient availability to the tumor, which we termed exercise induced metabolic-shield. Proteomic and ex-vivo metabolic-capacity analyses of mice internal organs revealed that exercise induces catabolic processes, glucose uptake, mitochondrial activity, and GLUT expression. Proteomic analysis of routinely active subjects' plasma demonstrated increased carbohydrate utilization following exercise. Further, epidemiological data of a 20-year follow-up of a large human cohort of cancer free participants, revealed that exercise prior to cancer initiation has a modest impact on cancer incidence in low metastatic stages, but significantly reduced the likelihood of highly metastatic cancer as compared to inactive participants. We utilized two exercise protocols, wherein the mice were subjected to exercise either both pre- and post- melanoma injection or only pre-injection. We found that exercise prior to cancer injection significantly protects against metastases in distant organs, regardless of the three melanoma metastases models we used. Mechanistically, ex-vivo inhibition of the mTOR pathway, via rapamycin treatment, reversed the protection from the exercise induced metabolic-shield. Under limited glucose conditions, active stroma consumed significantly more glucose, at the expense of the tumor, as reflected in histology analyses of mice melanoma metastases. Our data suggests that cancersâ€™ metabolic plasticity and the exercise-induced metabolic reprogramming of the stroma are clashing, raising the opportunity to block metastases by challenging cancersâ€™ metabolic needs.

INSTRUMENT(S): Q Exactive HF

ORGANISM(S): Homo Sapiens (human)

TISSUE(S): Blood Serum

SUBMITTER: Tamar Ziv

LAB HEAD: Carmit Levy

PROVIDER: PXD035648 | Pride | 2023-03-11

REPOSITORIES: Pride

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

Sheinboim Danna D Parikh Shivang S Manich Paulee P Markus Irit I Dahan Sapir S Parikh Roma R Stubbs Elisa E Cohen Gali G Zemser-Werner Valentina V Bell Rachel E RE Ruiz Sara Arciniegas SA Percik Ruth R Brenner Ronen R Leibou Stav S Vaknine Hananya H Arad Gali G Gerber Yariv Y Keinan-Boker Lital L Shimony Tal T Bikovski Lior L Goldstein Nir N Constantini Keren K Labes Sapir S Mordechai Shimonov S Doron Hila H Lonescu Ariel A Ziv Tamar T Nizri Eran E Choshen Guy G Eldar-Finkelman Hagit H Tabach Yuval Y Helman Aharon A Ben-Eliyahu Shamgar S Erez Neta N Perlson Eran E Geiger Tamar T Ben-Zvi Danny D Khaled Mehdi M Gepner Yftach Y Levy Carmit C

Cancer research 20221101 22

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 catabol ...[more]

PMID: 36084256

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Project description:Metabolic rewiring is essential for breast tumor growth and progression to metastatic disease, yet little is known regarding how cancer cells modify their acquired metabolic programs in response to different metastatic microenvironments. Transcriptional and metabolomic analysis have previously shown that liver-metastatic breast cancer cells adopt an intrinsic metabolic profile characterized by increased HIF-1α activity and dependence on glycolysis. Stable isotope tracing analysis (SITA) performed in vivo confirmed that the glycolytic nature of liver-metastatic breast cancer cells is retained when these cells are grown as primary tumors or as liver metastases. However, our data also reveal that unique metabolic adaptations are specifically induced by the liver microenvironment. Indeed, liver metastases display elevated expression of genes involved in glutathione (GSH) biosynthesis and reactive oxygen species (ROS) detoxification when compared to primary tumors. Moreover, breast cancer liver metastases rely strongly on glucose and glutamine-derived carbons to support de novo GSH synthesis. Glutathione is a tripeptide that acts as a major scavenger for reactive oxygen species (ROS). Liver metastases display reduced levels of 8-Oxo-2'-deoxyguanosine, confirming their increased capacity to buffer ROS. We demonstrated the dependence of liver metastases formation on these distinct metabolic adaptations by depleting glutamate-cysteine ligase (Gcl), the rate-limiting enzyme in glutathione biosynthesis. Gcl depletion, and decreased GSH levels, strongly reduced the capacity of liver-metastatic cells to form distant metastasis within the liver. We performed gene expression analysis of liver metastasis and primary tumors from liver-metastatic breast cancer cells derived from 4T1 cells. 4T1-2776 (76) and 4T1-2792 (92) cells were injected in the mammary fat pads of BALB/c and grown as primary tumors or were grown as liver metastasis after splenic injection. Tissues were harvested from primary tumors and liver metastasis and submitted to laser-capture microdissection (LCM). For liver metastasis, tumour tissue was harvested at 10 days, 2 weeks and 3 weeks after splenic injection. For each time point, tissue was isolated from the tumor centre (core), a peripheral area of the tumor (margin), a region of the liver proximal to the tumor (adjacent) and a region of the liver far from the tumor (distant). For primary tumors from 4T1-2776 cells (1034, 1036, 1043) and 4T1-2792 (MFP2L, MFP3L, MFP5L) tissue was collected from the tumor core and margin, at the experimental endpoint.

Project description:Circulating tumor cells (CTCs) are critical in the development of distant organ tumor metastasis, and are associated with advanced cancer stage and poor patient outcome. Here, we present the first genome-wide nucleotide-level characterization of CTCs. Our single-nucleotide polymorphism (SNP) analysis in patients with melanoma involved: 1) global comparative genomic analysis of CTCs and matched regional metastases, 2) identification of key genomic aberrations in CTCs, 3) verification of these target genes in aggressive distant tumor metastases, and 4) evidence of selective expression and functional consequence of CTC-associated genes in melanomas. We report 131 aberrant loci in CTCs that are potentially pro-metastatic, and show that such expression of a 5-marker gene panel (CSMD2, CNTNAP5, FLJ14051, ADAM6, TRPM2) in melanomas confers prognostic utility. Successful treatment of melanoma requires understanding of the metastatic process and identification of patients with tumors most likely to develop aggressive metastatic disease. Melanomas are heterogeneous, and CTCs have long been recognized as vehicles for cancer spread, representing particularly aggressive tumor clones that can evolve into successful clinical metastases. Elucidation of genomic aberrations in CTCs will aid in the development of prognostic biomarkers and therapeutic strategies to target CTCs to prevent or control distant cancer spread. This study provides the first detailed genomic confirmation of the close relation between CTCs and tumor metastases, and illustrates how CTCs can be utilized as a novel approach and rational source for identification of pro-metastatic genes in cancer research. Three individual patient cohorts were utilized in the study. CNV and LOH loci were evaluated initially in metastatic melanoma patients (n=13) in a discovery cohort. SNP loci that harbored CNV/LOH in CTCs were then separately verified for: (a) presence in distant organ metastasis (AJCC Stage IV melanoma) (n=27), and (b) relevance to prognosis in regional melanoma metastasis (AJCC Stage III melanoma) (n=35). The first discovery patient cohort group was utilized for capture of CTCs, and consisted of peripheral blood mononuclear cell (PBMC) and tumor specimens from metastatic melanoma patients (n=13). CTC-related loci were verified in a second cohort of patients with Stage IV distant organ metastases (n=27), including 15 brain, 4 lung, and 8 gastrointestinal (bowel, liver) metastases. The third patient cohort consisted of early passage (<12) established melanoma cell lines derived from 35 regional melanoma metastases (Stage III) for evaluation of the prognostic utility of the CTC-associated aberrant loci.

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