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Dynamic Phenotyping Reveals Highly Personalized, Integrated Host-Tumor Crosstalk During Exercise in Cancer Patients

ABSTRACT: How exercise therapy modulates the host systemic environment to regulate tumor evolution in humans is not known. We performed personalized, multiparametric, longitudinal profiling before, during, and after short-term endurance exercise in 13 patients with solid tumors in a preoperative “window” study. Time-series analyses revealed hundreds of host molecular changes in the plasma metabolome and proteome and gut microbiome involved in a diverse-array of biological processes. Host systemic environmental changes were paralleled by modulation of core tumor gene expression pathways notably tumor cell cycle regulation, stress response, and metabolism. Integrative network analyses revealed the complexity of the host – tumor interaction under exercise regulation, elucidating novel mechanistic insights. Variability at baseline and during intervention highlighted highly personalized responses to uniform exercise therapy. Our study provides an example of how generation of a longitudinal high-definition dataset provides a framework for interrogation of the integrative, host-tissue response to exercise in clinical populations.

ORGANISM(S): human gut metagenome

PROVIDER: GSE325533 | GEO | 2026/03/23

REPOSITORIES: GEO

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Project description:Aberrant production and/or function of multiple host systemic factors (e.g., metabolic and immune-inflammatory mediators) act in concert to promote a âtumorigenicâ host milieu that directly promotes an aggressive malignant phenotype as well as drug resistance. Hence, strategies with the capacity to simultaneously act across multiple host systemic pathways may be required to optimize therapeutic outcomes in solid tumors. We hypothesized that chronic aerobic training, a pleiotropic whole-body intervention, modulates multiple systemic host pathways that, in turn, effectively alters cancer cell phenotype in vitro. Plasma samples from patients with solid tumors exposed to chronic aerobic training or sedentary control were comprehensively characterized for changes in immune, inflammatory, and metabolic pathways. Compared with sedentary control, aerobic training caused significant reductions in interleukin (IL)-4, macrophage inflammatory protein-1 beta (MIP1-Î²), vascular endothelial growth factor (VEGF), tumor necrosis factor-alpha (TNF-Î±), and hepatocyte growth factor (HGF). There were no significant changes in leukocyte phenotype or any plasma metabolite signatures. Exposure of estrogen receptor (ER) distinct human breast cancer cell lines (MCF-7 and MDA-MB-231) to post-intervention serum from breast cancer patients exposed to aerobic training caused marked increases in proliferation, migration, and apoptosis, compared to control patient serum. Only the combination of cytokines significantly reduced in plasma following aerobic training recapitulated the phenotype observed with patient serum in MCF-7 cells whereas only the single addition of MIP-1Î² or HGF significantly increased apoptosis in MDA-MB-231 cells. Co-culturing of MDA-MB-231 cells with patient exercise serum and a HGF neutralizing antibody increased proliferation and completely abrogated exercise serum-induced apoptosis. Finally, whole-genome microarray of MDA-MB-231 cells exposed to exercise or control patient serum revealed differential modulation of 310 genes including PTEN, CDK3, and IGFBP1. Our findings indicate the widespread potential of chronic aerobic training to modulate host immune-inflammatory systemic factors in patients with solid tumors. Modulation of such pathways directly alters breast cancer phenotypes providing novel insight into the molecular pathways by which exercise may inhibit malignant progression. MDA-MB-231 cells were plated at 250,000 cells/well in triplicate with 10% FBS in 6-well plates and left overnight to adhere. Media was suctioned off and replaced with serum free media. Patient serum was then added to the wells at a 10% final concentration and RNA was harvested using Qiagen RNeasy kit after 4 days.

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Dynamic Phenotyping Reveals Highly Personalized, Integrated Host-Tumor Crosstalk During Exercise in Cancer Patients

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