An FGF21-IGFBP1 tumor-liver relay drives musculoskeletal defects in colorectal cancer cachexia
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.
Authors
- Nicholas A. Jamnick (ORCID: https://orcid.org/0000-0003-0890-2853)
- Ronald J. Sokol (ORCID: https://orcid.org/0000-0001-7433-4095)
- Michael W. Devereaux (ORCID: https://orcid.org/0000-0003-0140-8756)
- C. Gammon
- Aimee L. Anderson (ORCID: https://orcid.org/0000-0002-2464-5343)
- Alyson L. Essex (ORCID: https://orcid.org/0000-0001-7698-5342)
- Leah J. Novinger (ORCID: https://orcid.org/0000-0002-9018-7838)
- Fabrizio Pin (ORCID: https://orcid.org/0000-0002-3562-8629)
- Chandler S. Callaway (ORCID: https://orcid.org/0000-0002-4562-0508)
- Paul A. Roberson (ORCID: https://orcid.org/0000-0001-7696-7398)
- Douglas J. Adams (ORCID: https://orcid.org/0000-0002-6090-0516)
- Andrea Bonetto (ORCID: https://orcid.org/0000-0002-3235-1871)
- Bifeng Gao
- Patrick D. Livingston
- Natalia M. Weinzierl
- Meher P. Boorgula
- Joshua R. Huot (ORCID: https://orcid.org/0000-0002-8632-5791)
- COLIN T. SHEARN
- Jing Xu
- Andrew Goodspeed
- Urja R. Kamdar
- Luis Felipe Cardona Polo
- Schuyler Lee
Institutions
- Indiana University Health (US)
- University of Colorado Cancer Center (US)
- Indiana University School of Medicine
- University of Colorado Anschutz Medical Campus (US)
- Indiana University – Purdue University Indianapolis (US)
- University of Colorado Denver (US)
Publication Details
- Journal
- Nature Communications
- Published
- 2026-08-27
- DOI
- https://doi.org/10.1038/s41467-026-77305-6
- Primary Topic
- Fibroblast Growth Factor Research
- Type
- article
- Field-Weighted Citation Impact
- 0.00
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