An FGF21-IGFBP1 tumor-liver relay drives musculoskeletal defects in colorectal cancer cachexia
Year: 2026
Type: article
Abstract: Colorectal cancer (CRC) is frequently accompanied by cachexia, a wasting syndrome characterized by progressive loss of muscle and bone that worsens physical function and survival. Although liver dysfunction is increasingly recognized in cachexia, whether tumor-induced liver signaling contributes directly to musculoskeletal decline remains unclear. Here we show that CRC establishes a tumor-liver endocrine relay in which tumor-derived fibroblast growth factor 21 (FGF21) stimulates hepatic production of the hepatokine insulin-like growth factor binding protein 1 (IGFBP1). IGFBP1 is consistently elevated in patients with CRC and in multiple mouse models, where it promotes osteoclast differentiation, muscle atrophy, and bone loss. Genetic or pharmacological inhibition of IGFBP1 preserves muscle and bone despite persistent tumor burden, whereas deletion of tumor-derived FGF21 suppresses hepatic IGFBP1 production and mitigates musculoskeletal wasting. These findings identify a tumor-liver signaling axis that drives CRC-associated cachexia and highlight the FGF21-IGFBP1 pathway as a therapeutic target to preserve musculoskeletal health.
Source: Nature Communications
Authors: Joshua R. Huot, Urja R. Kamdar, Caleb J. Gammon, Patrick D. Livingston, Fabrizio Pin, Nicholas A. Jamnick, Natalia M. Weinzierl, Chandler S. Callaway, Paul A. Roberson, Alyson L. Essex, Jing Xu, Luis Felipe Cardona Polo, Michael W. Devereaux, Aimee L. Anderson, Colin T. Shearn, Ronald J. Sokol, Schuyler Lee, Bifeng Gao, Meher P. Boorgula, Andrew Goodspeed, Leah J. Novinger, Douglas J. Adams, Andrea Bonetto
Language: English
Subfield: Molecular Biology
Domain: Life Sciences
Open Access status: gold
Estimated APC paid: $6,990
Funders: National Science Foundation, American Cancer Society, Indiana Clinical and Translational Sciences Institute, Colorado State University, Cancer League of Colorado, China Scholarship Council, National Institutes of Health, University of Colorado Boulder, School of Medicine, Indiana University, Nutrition Obesity Research Center, University of North Carolina, National Cancer Institute, National Institute of Diabetes and Digestive and Kidney Diseases, National Institute of Arthritis and Musculoskeletal and Skin Diseases
Awards: G1067951072, G1126835621, G140742271, G1559658584, G1589937986, G1625418467, G2306885769, G3048487988, G324030696, G3428164765, G3754633476, Mechanisms of Muscle Weakness During Cancer Survivorship, G4437163022, G4533328248, G5424111711, G5919981984, G5926543585, G6500554123, CC* Compute: HPC Services for the Colorado State University System, G7312021790, G8067353062, G8220025418, IGFBP1 mediates a liver-bone-muscle axis in colorectal cancer cachexia, University of Colorado Cancer Center Support Grant, Interdisciplinary Training in Musculoskeletal Research, Comprehensive Musculoskeletal Training Program
OpenAlex ID: W7204471806
FWCI:
Cites:
Cited by:
Related to: