Journal article
Metabolic Dysregulation Explains the Diverse Impacts of Obesity in Males and Females with Gastrointestinal Cancers
International journal of molecular sciences, Vol.24(13), 10847
06/29/2023
DOI: 10.3390/ijms241310847
PMCID: PMC10342094
PMID: 37446025
Abstract
The prevalence of obesity, defined as the body mass index (BMI) & GE; 30 kg/m(2), 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 < 0.05 and |logFC| > 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.
Details
- Title: Subtitle
- Metabolic Dysregulation Explains the Diverse Impacts of Obesity in Males and Females with Gastrointestinal Cancers
- Creators
- Spencer R. Rosario - Roswell Park Comprehensive Cancer CenterBowen Dong - Roswell Park Comprehensive Cancer CenterYali Zhang - Roswell Park Comprehensive Cancer CenterHua-Hsin Hsiao - Roswell Pk Comprehens Canc Ctr, Dept Biostat & Bioinformat, Buffalo, NY 14203 USAEmily Isenhart - Roswell Park Comprehensive Cancer CenterJianmin Wang - Roswell Park Comprehensive Cancer CenterErin M. Siegel - Moffitt Cancer CenterArta M. Monjazeb - University of California, DavisDwight H. Owen - The Ohio State UniversityPrasenjit Dey - Roswell Park Comprehensive Cancer CenterFred K. Tabung - The Ohio State UniversityDaniel J. Spakowicz - The Ohio State UniversityWilliam J. Murphy - University of California, DavisStephen Edge - Roswell Park Comprehensive Cancer CenterSai Yendamuri - Roswell Park Comprehensive Cancer CenterSami Ibrahimi - University of Oklahoma Health Sciences CenterJill M. Kolesar - University of KentuckyPatsy H. McDonald - H Lee Moffitt Canc Ctr & Res Inst, Dept Canc Biol, Tampa, FL 33612 USADeepak Vadehra - Roswell Park Comprehensive Cancer CenterMichelle ChurchmanSong Liu - Roswell Park Comprehensive Cancer CenterPawel Kalinski - Roswell Pk Comprehens Canc Ctr, Dept Immunol, Buffalo, NY 14203 USASarbajit Mukherjee - Roswell Park Comprehensive Cancer Center
- Resource Type
- Journal article
- Publication Details
- International journal of molecular sciences, Vol.24(13), 10847
- Publisher
- Mdpi
- DOI
- 10.3390/ijms241310847
- PMID
- 37446025
- PMCID
- PMC10342094
- ISSN
- 1661-6596
- eISSN
- 1422-0067
- Number of pages
- 17
- Grant note
- U24CA274159 / ARTNet: Coordinating and Data Management Center U24CA232979 / IOTN: Data Management and Resource-Sharing Center R25CA203650 / TREC Fellowship Training Workshop
- Language
- English
- Date published
- 06/29/2023
- Academic Unit
- Pharmacy; Pharmaceutical Sciences and Experimental Therapeutics
- Record Identifier
- 9984696542602771
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