{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,18]],"date-time":"2026-08-18T04:48:37Z","timestamp":1787028517893,"version":"build-2736575974"},"reference-count":38,"publisher":"MDPI AG","issue":"13","license":[{"start":{"date-parts":[[2023,6,29]],"date-time":"2023-06-29T00:00:00Z","timestamp":1687996800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"This work was supported by the IOTN: Data Management and Resource-Sharing Center (U24CA232979, S.R.R.), the TREC Fellowship Training Workshop (R25CA203650 (PI: Melinda Irwin); S.R.R.).","award":["n\/a"],"award-info":[{"award-number":["n\/a"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>The prevalence of obesity, defined as the body mass index (BMI) \u2265 30 kg\/m2, has reached epidemic levels. Obesity is associated with an increased risk of various cancers, including gastrointestinal ones. Recent evidence has suggested that obesity disproportionately impacts males and females with cancer, resulting in varied transcriptional and metabolic dysregulation. This study aimed to elucidate the differences in the metabolic milieu of adenocarcinomas of the gastrointestinal (GI) tract both related and unrelated to sex in obesity. To demonstrate these obesity and sex-related effects, we utilized three primary data sources: serum metabolomics from obese and non-obese patients assessed via the Biocrates MxP Quant 500 mass spectrometry-based kit, the ORIEN tumor RNA-sequencing data for all adenocarcinoma cases to assess the impacts of obesity, and publicly available TCGA transcriptional analysis to assess GI cancers and sex-related differences in GI cancers specifically. We applied and integrated our unique transcriptional metabolic pipeline in combination with our metabolomics data to reveal how obesity and sex can dictate differential metabolism in patients. Differentially expressed genes (DEG) analysis of ORIEN obese adenocarcinoma as compared to normal-weight adenocarcinoma patients resulted in large-scale transcriptional reprogramming (4029 DEGs, adj. p &lt; 0.05 and |logFC| &gt; 0.58). Gene Set Enrichment and metabolic pipeline analysis showed genes enriched for pathways relating to immunity (inflammation, and CD40 signaling, among others) and metabolism. Specifically, we found alterations to steroid metabolism and tryptophan\/kynurenine metabolism in obese patients, both of which are highly associated with disease severity and immune cell dysfunction. These findings were further confirmed using the TCGA colorectal adenocarcinoma (CRC) and esophageal adenocarcinoma (ESCA) data, which showed similar patterns of increased tryptophan catabolism for kynurenine production in obese patients. These patients further showed disparate alterations between males and females when comparing obese to non-obese patient populations. Alterations to immune and metabolic pathways were validated in six patients (two obese and four normal weight) via CD8+\/CD4+ peripheral blood mononuclear cell RNA-sequencing and paired serum metabolomics, which showed differential kynurenine and lipid metabolism, which corresponded with altered T-cell transcriptome in obese populations. Overall, obesity is associated with differential transcriptional and metabolic programs in various disease sites. Further, these alterations, such as kynurenine and tryptophan metabolism, which impact both metabolism and immune phenotype, vary with sex and obesity together. This study warrants further in-depth investigation into obesity and sex-related alterations in cancers that may better define biomarkers of response to immunotherapy.<\/jats:p>","DOI":"10.3390\/ijms241310847","type":"journal-article","created":{"date-parts":[[2023,6,30]],"date-time":"2023-06-30T00:43:30Z","timestamp":1688085810000},"page":"10847","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":13,"title":["Metabolic Dysregulation Explains the Diverse Impacts of Obesity in Males and Females with Gastrointestinal Cancers"],"prefix":"10.3390","volume":"24","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-2626-9257","authenticated-orcid":false,"given":"Spencer R.","family":"Rosario","sequence":"first","affiliation":[{"name":"Department of Biostatistics and Bioinformatics, Roswell Park Comprehensive Cancer Center, Buffalo, NY 14203, USA"},{"name":"Department of Pharmacology and Therapeutics, Roswell Park Comprehensive Cancer Center, Buffalo, NY 14203, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bowen","family":"Dong","sequence":"additional","affiliation":[{"name":"Department of Immunology, Roswell Park Comprehensive Cancer Center, Buffalo, NY 14203, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yali","family":"Zhang","sequence":"additional","affiliation":[{"name":"Department of Biostatistics and Bioinformatics, Roswell Park Comprehensive Cancer Center, Buffalo, NY 14203, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hua-Hsin","family":"Hsiao","sequence":"additional","affiliation":[{"name":"Department of Biostatistics and Bioinformatics, Roswell Park Comprehensive Cancer Center, Buffalo, NY 14203, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Emily","family":"Isenhart","sequence":"additional","affiliation":[{"name":"Department of Biostatistics and Bioinformatics, Roswell Park Comprehensive Cancer Center, Buffalo, NY 14203, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jianmin","family":"Wang","sequence":"additional","affiliation":[{"name":"Department of Biostatistics and Bioinformatics, Roswell Park Comprehensive Cancer Center, Buffalo, NY 14203, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1779-2510","authenticated-orcid":false,"given":"Erin M.","family":"Siegel","sequence":"additional","affiliation":[{"name":"Department of Cancer Epidemiology, H. Lee Moffitt Cancer Center, Tampa, FL 33612, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Arta M.","family":"Monjazeb","sequence":"additional","affiliation":[{"name":"Department of Radiation Oncology, University of California Davis, Sacramento, CA 95616, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dwight H.","family":"Owen","sequence":"additional","affiliation":[{"name":"Department of Medical Oncology, Ohio State University Comprehensive Cancer Center, Columbus, OH 43210, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Prasenjit","family":"Dey","sequence":"additional","affiliation":[{"name":"Department of Immunology, Roswell Park Comprehensive Cancer Center, Buffalo, NY 14203, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8193-7150","authenticated-orcid":false,"given":"Fred K.","family":"Tabung","sequence":"additional","affiliation":[{"name":"Department of Epidemiology, Ohio State University Comprehensive Cancer Center, Columbus, OH 43210, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2314-6435","authenticated-orcid":false,"given":"Daniel J.","family":"Spakowicz","sequence":"additional","affiliation":[{"name":"Department of Medical Oncology, Ohio State University Comprehensive Cancer Center, Columbus, OH 43210, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"William J.","family":"Murphy","sequence":"additional","affiliation":[{"name":"Department of Immunology, University of California Davis, Sacramento, CA 95616, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Stephen","family":"Edge","sequence":"additional","affiliation":[{"name":"Department of Surgical Oncology, Roswell Park Comprehensive Cancer Center, Buffalo, NY 14203, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sai","family":"Yendamuri","sequence":"additional","affiliation":[{"name":"Department of Thoracic Surgery, Roswell Park Comprehensive Cancer Center, Buffalo, NY 14203, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sami","family":"Ibrahimi","sequence":"additional","affiliation":[{"name":"Department of Medicine, Oklahoma University Health Stephenson Cancer Center, Oklahoma City, OK 73104, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1802-6439","authenticated-orcid":false,"given":"Jill M.","family":"Kolesar","sequence":"additional","affiliation":[{"name":"Department of Pharmacy, University of Kentucky College of Pharmacy, Lexington, KY 40506, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Patsy H.","family":"McDonald","sequence":"additional","affiliation":[{"name":"Department of Cancer Biology, Moffitt Cancer Center, Tampa, FL 33612, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Deepak","family":"Vadehra","sequence":"additional","affiliation":[{"name":"Department of Medicine, Roswell Park Comprehensive Cancer Center, Buffalo, NY 14203, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Michelle","family":"Churchman","sequence":"additional","affiliation":[{"name":"Precision Therapy and Diagnostics, Aster Insights, Hudson, FL 34667, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Song","family":"Liu","sequence":"additional","affiliation":[{"name":"Department of Biostatistics and Bioinformatics, Roswell Park Comprehensive Cancer Center, Buffalo, NY 14203, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Pawel","family":"Kalinski","sequence":"additional","affiliation":[{"name":"Department of Immunology, Roswell Park Comprehensive Cancer Center, Buffalo, NY 14203, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sarbajit","family":"Mukherjee","sequence":"additional","affiliation":[{"name":"Department of Immunology, Roswell Park Comprehensive Cancer Center, Buffalo, NY 14203, USA"},{"name":"Department of Medicine, Roswell Park Comprehensive Cancer Center, Buffalo, NY 14203, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2023,6,29]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"2050312120918265","DOI":"10.1177\/2050312120918265","article-title":"The obesity epidemic\u2014Nature via nurture: A narrative review of high-income countries","volume":"8","author":"Jackson","year":"2020","journal-title":"SAGE Open Med."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"1431","DOI":"10.1038\/ijo.2008.102","article-title":"Global burden of obesity in 2005 and projections to 2030","volume":"32","author":"Kelly","year":"2008","journal-title":"Int. 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