{"doi":"10.1101/2025.06.19.660576","title":"Obesity promotes conserved inflammatory and metabolic transcriptional programs in mouse and human colon tumors","abstract":"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. Objective 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 two species. Methods We employed a mouse colon cancer model with colonoscopy-guided orthotopic transplantation of syngeneic Apc-null;KrasG12D/+;Trp53-null;Smad4-null;tdTomato 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 ColoCare 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 upregulation of genes involved in innate immune sensing ( TLR2 , MYD88 , IRF4 ) and tumor microenvironment remodeling ( MMP9 , TGFB1 , SERPINE1 ). Analysis of paired mesenteric visceral adipose tissue and tumor samples from the ColoCare cohort indicated that obesity amplifies inflammatory signaling pathways through unique adipose ligand-tumor receptor interactions. Conclusions These results establish obesity-associated adipose tissue dysregulation as a key inter-tissue modulator of biology, with concordant cross-species effects on tumor cell-intrinsic inflammatory and metabolic programs.","journal":"bioRxiv (Cold Spring Harbor Laboratory)","year":2025,"id":569098,"datarank":0.0,"base_score":0.0,"endowment":0.0,"self_citation_contribution":0.0,"citation_network_contribution":0.0,"self_endowment_contribution":0.0,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":0,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9538,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2025-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":392589,"name":"Tengda Lin","orcid":"0000-0001-5147-8432","position":1,"is_corresponding":false},{"id":1403576,"name":"Victoria M. 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Li","orcid":"0000-0003-1543-0743","position":27,"is_corresponding":false},{"id":104598,"name":"Jane C. Figueiredo","orcid":"0000-0002-2452-3194","position":28,"is_corresponding":false},{"id":261753,"name":"Aik Choon Tan","orcid":"0000-0003-2955-8369","position":29,"is_corresponding":false},{"id":64920,"name":"Jatin Roper","orcid":"0000-0002-8851-1352","position":30,"is_corresponding":false},{"id":392604,"name":"Alexis Ulrich","orcid":"0000-0003-1469-2186","position":31,"is_corresponding":false},{"id":392606,"name":"Stephen D. Hursting","orcid":"0000-0003-3605-2833","position":32,"is_corresponding":false},{"id":353018,"name":"Elaine M. Glenny","orcid":"0000-0002-1024-4290","position":0,"is_corresponding":true}],"reference_count":51,"raw_metadata":null,"created_at":"2026-07-19T02:56:59.652443Z","pmid":"40667217","pmcid":null,"fwci":null,"citation_percentile":null,"influential_citations":0,"oa_status":null,"license":null,"views":0,"total_file_size_bytes":0,"version_count":0,"fair_f":null,"fair_a":null,"fair_i":null,"fair_r":null,"fair_zscore":null,"fair_rationale":null,"fair_model":null,"fair_agent_version":null,"fair_fulltext_source":null,"fair_has_llm":null,"fair_computed_at":null,"clinical_trials":[],"software_tools":[],"db_accessions":[],"linked_datasets":[],"topics":[]}