Obesity promotes conserved inflammatory and metabolic transcriptional programs in colon tumors: evidence from mouse models and the ColoCare Study Patient Cohort

Elaine M Glenny¹, Tengda Lin², Victoria M Bandera², Babak Mirminachi³, Saratchandra S Khumukcham³, Biljana Gigic⁴, Christy A Warby², Olena Aksonova², Michael F Coleman¹, Alessandro Carpanese³, Calista Busch³, Caroline Himbert², Jennifer Ose⁵, David A Nix⁶, Kenneth Boucher⁷, Peter Schirmacher⁸, Ildiko Strehli⁹, Sheetal Hardikar², Jessica N Cohan⁹, Jolanta Jedrzkiewicz¹⁰, Alexander Brobeil⁸, Martin A Schneider¹¹, Christoph Kahlert⁴, Erin M Siegel¹², Doratha A Byrd¹², Adetunji T Toriola¹³, David Shibata¹⁴, Christopher I Li¹⁵, Jane C Figueiredo¹⁶, Aik Choon Tan¹⁷, Jatin Roper¹⁸, Cornelia M Ulrich¹⁹, Stephen D Hursting²⁰

Affiliations

¹ Department of Nutrition, University of North Carolina at Chapel Hill, Chapel Hill, NC, United States.
² Department of Population Health Sciences, University of Utah, Salt Lake City, UT, United States; Huntsman Cancer Institute, University of Utah, Salt Lake City, UT, United States.
³ Division of Gastroenterology, Department of Medicine, Duke University, Durham, NC, United States.
⁴ Department of General, Visceral, and Transplantation Surgery, Heidelberg University Hospital, Heidelberg, Germany.
⁵ Department of Population Health Sciences, University of Utah, Salt Lake City, UT, United States; Huntsman Cancer Institute, University of Utah, Salt Lake City, UT, United States; Department of Information and Communication, University of Applied Sciences and Arts, Hannover, Germany.
⁶ Cancer Bioinformatics Shared Resource, Huntsman Cancer Institute, Salt Lake City, UT, United States.
⁷ Cancer Biostatistics Shared Resource, Huntsman Cancer Institute, Division of Epidemiology, University of Utah, Salt Lake City, UT, United States.
⁸ Institute of Pathology, Heidelberg University Hospital, Heidelberg, Germany.
⁹ Huntsman Cancer Institute, University of Utah, Salt Lake City, UT, United States.
¹⁰ Huntsman Cancer Institute, University of Utah, Salt Lake City, UT, United States; Department of Pathology, Huntsman Cancer Institute, Salt Lake City, UT, United States.
¹¹ Department of General, Visceral, and Transplantation Surgery, Heidelberg University Hospital, Heidelberg, Germany; Klinik für Allgemein-, Viszeral- Thorax-, Transplantations- und Kinderchirurgie, Universitätsklinikum Gießen und Marburg GmbH, Heidelberg, Germany.
¹² Department of Cancer Epidemiology, H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL, United States.
¹³ Division of Public Health Sciences, Department of Surgery, Washington University School of Medicine, St. Louis, MO, United States; Siteman Cancer Center, Washington University School of Medicine, St. Louis, MO, United States.
¹⁴ Department of Surgery, University of Tennessee Health Science Center, Memphis, TN, United States.
¹⁵ Division of Public Health Sciences, Fred Hutchinson Cancer Center, Seattle, WA, United States.
¹⁶ Department of Medicine, Cedars-Sinai Medical Center, Los Angeles, CA, United States; Samuel Oschin Comprehensive Cancer Institute, Cedars-Sinai Medical Center, Los Angeles, CA, United States.
¹⁷ Huntsman Cancer Institute, University of Utah, Salt Lake City, UT, United States; Cancer Bioinformatics Shared Resource, Huntsman Cancer Institute, Salt Lake City, UT, United States; Departments of Oncological Sciences and Biomedical Informatics, University of Utah, Salt Lake City, UT, United States.
¹⁸ Division of Gastroenterology, Department of Medicine, Duke University, Durham, NC, United States; Department of Pharmacology and Cancer Biology, Duke University, Durham, NC, United States; Department of Cell Biology, Duke University, Durham, NC, United States. Electronic address: jatin.roper@duke.edu.
¹⁹ Department of Population Health Sciences, University of Utah, Salt Lake City, UT, United States; Huntsman Cancer Institute, University of Utah, Salt Lake City, UT, United States. Electronic address: neli.ulrich@hci.utah.edu.
²⁰ Department of Nutrition, University of North Carolina at Chapel Hill, Chapel Hill, NC, United States; Nutrition Research Institute, University of Carolina at Chapel Hill, Kannapolis, NC, United States; Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, NC, United States. Electronic address: hursting@email.unc.edu.

PMID: 40998019
DOI: 10.1016/j.ajcnut.2025.09.031

Free article

Obesity promotes conserved inflammatory and metabolic transcriptional programs in colon tumors: evidence from mouse models and the ColoCare Study Patient Cohort

Elaine M Glenny et al. Am J Clin Nutr. 2025 Dec.

Free article

. 2025 Dec;122(6):1545-1556.

doi: 10.1016/j.ajcnut.2025.09.031. Epub 2025 Sep 24.

Authors

Affiliations

¹ Department of Nutrition, University of North Carolina at Chapel Hill, Chapel Hill, NC, United States.
² Department of Population Health Sciences, University of Utah, Salt Lake City, UT, United States; Huntsman Cancer Institute, University of Utah, Salt Lake City, UT, United States.
³ Division of Gastroenterology, Department of Medicine, Duke University, Durham, NC, United States.
⁴ Department of General, Visceral, and Transplantation Surgery, Heidelberg University Hospital, Heidelberg, Germany.
⁵ Department of Population Health Sciences, University of Utah, Salt Lake City, UT, United States; Huntsman Cancer Institute, University of Utah, Salt Lake City, UT, United States; Department of Information and Communication, University of Applied Sciences and Arts, Hannover, Germany.
⁶ Cancer Bioinformatics Shared Resource, Huntsman Cancer Institute, Salt Lake City, UT, United States.
⁷ Cancer Biostatistics Shared Resource, Huntsman Cancer Institute, Division of Epidemiology, University of Utah, Salt Lake City, UT, United States.
⁸ Institute of Pathology, Heidelberg University Hospital, Heidelberg, Germany.
⁹ Huntsman Cancer Institute, University of Utah, Salt Lake City, UT, United States.
¹⁰ Huntsman Cancer Institute, University of Utah, Salt Lake City, UT, United States; Department of Pathology, Huntsman Cancer Institute, Salt Lake City, UT, United States.
¹¹ Department of General, Visceral, and Transplantation Surgery, Heidelberg University Hospital, Heidelberg, Germany; Klinik für Allgemein-, Viszeral- Thorax-, Transplantations- und Kinderchirurgie, Universitätsklinikum Gießen und Marburg GmbH, Heidelberg, Germany.
¹² Department of Cancer Epidemiology, H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL, United States.
¹³ Division of Public Health Sciences, Department of Surgery, Washington University School of Medicine, St. Louis, MO, United States; Siteman Cancer Center, Washington University School of Medicine, St. Louis, MO, United States.
¹⁴ Department of Surgery, University of Tennessee Health Science Center, Memphis, TN, United States.
¹⁵ Division of Public Health Sciences, Fred Hutchinson Cancer Center, Seattle, WA, United States.
¹⁶ Department of Medicine, Cedars-Sinai Medical Center, Los Angeles, CA, United States; Samuel Oschin Comprehensive Cancer Institute, Cedars-Sinai Medical Center, Los Angeles, CA, United States.
¹⁷ Huntsman Cancer Institute, University of Utah, Salt Lake City, UT, United States; Cancer Bioinformatics Shared Resource, Huntsman Cancer Institute, Salt Lake City, UT, United States; Departments of Oncological Sciences and Biomedical Informatics, University of Utah, Salt Lake City, UT, United States.
¹⁸ Division of Gastroenterology, Department of Medicine, Duke University, Durham, NC, United States; Department of Pharmacology and Cancer Biology, Duke University, Durham, NC, United States; Department of Cell Biology, Duke University, Durham, NC, United States. Electronic address: jatin.roper@duke.edu.
¹⁹ Department of Population Health Sciences, University of Utah, Salt Lake City, UT, United States; Huntsman Cancer Institute, University of Utah, Salt Lake City, UT, United States. Electronic address: neli.ulrich@hci.utah.edu.
²⁰ Department of Nutrition, University of North Carolina at Chapel Hill, Chapel Hill, NC, United States; Nutrition Research Institute, University of Carolina at Chapel Hill, Kannapolis, NC, United States; Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, NC, United States. Electronic address: hursting@email.unc.edu.

PMID: 40998019
DOI: 10.1016/j.ajcnut.2025.09.031

Abstract

Background: The global prevalence of obesity, an established risk and progression factor for colon cancer, is high and rising. Unfortunately, the mechanisms underlying the obesity-colon cancer association are incompletely understood, and new molecular targets enabling more effective intervention strategies to break the obesity-colon cancer link are urgently needed.

Objectives: This study integrated RNA sequencing data from mouse and human colon tumor samples, as well as human adipose samples, to rigorously establish obesity-associated transcriptomic signatures conserved between the 2 species.

Methods: We employed a mouse colon cancer model with colonoscopy-guided orthotopic transplantation of syngeneic Apc^nullKras^G12D/+Trp53^nullSmad4^nulltdTomato colon tumor organoids. Epithelial cell adhesion molecule (EpCAM)-positive cells from murine tumors and 193 human colon tumors and 188 human mesenteric adipose tissue samples from the prospective ColoCare Study cohort underwent transcriptomic analyses.

Results: Diet-induced obesity reduced survival in the mouse model of colon cancer. Integrated transcriptomic analyses of EpCAM-positive murine tumor cells and bulk human tumors revealed obesity-driven enrichment of inflammation and metabolic pathways, including the upregulation of genes involved in innate immune sensing (TLR2, MYD88, and IRF4) and tumor microenvironment remodeling (MMP9, TGFB1, and SERPINE1). Analysis of paired mesenteric visceral adipose tissue and tumor samples from the study patients (63 ± 13 y, 48% female, body mass index 28.9 ± 6.0 kg/m²) indicated that obesity was associated with enriched inflammatory signaling pathways through unique adipose ligand-tumor receptor interactions.

Conclusions: These results establish obesity-associated adipose tissue dysregulation as a key intertissue modulator of biology, with concordant cross-species effects on tumor cell-intrinsic inflammatory and metabolic programs.

Keywords: RNA sequencing; colon cancer; inflammation; ligand-receptor interactions; metabolism; obesity; visceral adipose tissue.

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Conflict of interest statement

Conflict of interest CMU has as cancer center director oversight research funded by several pharmaceutical companies but has not received funding directly herself. All other authors report no conflicts of interest.

Update of

Obesity promotes conserved inflammatory and metabolic transcriptional programs in mouse and human colon tumors.
Glenny EM, Lin T, Bandera VM, Mirminachi B, Khumukcham SS, Gigic B, Warby CA, Aksonova O, Coleman MF, Carpanese A, Busch C, Himbert C, Ose J, Nix DA, Boucher K, Schirmacher P, Strehli I, Hardikar S, Cohan JN, Jedrzkiewicz J, Brobeil A, Schneider MA, Kahlert C, Siegel EM, Byrd DA, Toriola AT, Shibata D, Li CI, Figueiredo JC, Tan AC, Roper J, Ulrich CM, Hursting SD. Glenny EM, et al. bioRxiv [Preprint]. 2025 Jun 25:2025.06.19.660576. doi: 10.1101/2025.06.19.660576. bioRxiv. 2025. Update in: Am J Clin Nutr. 2025 Dec;122(6):1545-1556. doi: 10.1016/j.ajcnut.2025.09.031. PMID: 40667217 Free PMC article. Updated. Preprint.

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Obesity promotes conserved inflammatory and metabolic transcriptional programs in colon tumors: evidence from mouse models and the ColoCare Study Patient Cohort

Affiliations

Obesity promotes conserved inflammatory and metabolic transcriptional programs in colon tumors: evidence from mouse models and the ColoCare Study Patient Cohort

Authors

Affiliations

Abstract

Conflict of interest statement

Update of

MeSH terms

LinkOut - more resources

Full Text Sources

Medical

Research Materials

Miscellaneous