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© 2023 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/). Notwithstanding the ProQuest Terms and Conditions, you may use this content in accordance with the terms of the License.

Abstract

The prevalence of obesity, defined as the body mass index (BMI) ≥ 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 < 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
Metabolic Dysregulation Explains the Diverse Impacts of Obesity in Males and Females with Gastrointestinal Cancers
Author
Rosario, Spencer R 1   VIAFID ORCID Logo  ; Bowen, Dong 2 ; Zhang, Yali 3 ; Hua-Hsin Hsiao 3 ; Isenhart, Emily 3 ; Wang, Jianmin 3 ; Siegel, Erin M 4   VIAFID ORCID Logo  ; Monjazeb, Arta M 5 ; Owen, Dwight H 6 ; Dey, Prasenjit 2 ; Tabung, Fred K 7   VIAFID ORCID Logo  ; Spakowicz, Daniel J 6   VIAFID ORCID Logo  ; Murphy, William J 8 ; Edge, Stephen 9 ; Yendamuri, Sai 10 ; Ibrahimi, Sami 11 ; Kolesar, Jill M 12   VIAFID ORCID Logo  ; McDonald, Patsy H 13 ; Vadehra, Deepak 14 ; Churchman, Michelle 15 ; Liu, Song 3 ; Kalinski, Pawel 2 ; Mukherjee, Sarbajit 16 

 Department of Biostatistics and Bioinformatics, Roswell Park Comprehensive Cancer Center, Buffalo, NY 14203, USA; [email protected] (S.R.R.); [email protected] (Y.Z.); [email protected] (H.-H.H.); [email protected] (E.I.); [email protected] (J.W.); [email protected] (S.L.); Department of Pharmacology and Therapeutics, Roswell Park Comprehensive Cancer Center, Buffalo, NY 14203, USA 
 Department of Immunology, Roswell Park Comprehensive Cancer Center, Buffalo, NY 14203, USA; [email protected] (B.D.); [email protected] (P.D.); [email protected] (P.K.) 
 Department of Biostatistics and Bioinformatics, Roswell Park Comprehensive Cancer Center, Buffalo, NY 14203, USA; [email protected] (S.R.R.); [email protected] (Y.Z.); [email protected] (H.-H.H.); [email protected] (E.I.); [email protected] (J.W.); [email protected] (S.L.) 
 Department of Cancer Epidemiology, H. Lee Moffitt Cancer Center, Tampa, FL 33612, USA; [email protected] 
 Department of Radiation Oncology, University of California Davis, Sacramento, CA 95616, USA; [email protected] 
 Department of Medical Oncology, Ohio State University Comprehensive Cancer Center, Columbus, OH 43210, USA; [email protected] (D.H.O.); [email protected] (D.J.S.) 
 Department of Epidemiology, Ohio State University Comprehensive Cancer Center, Columbus, OH 43210, USA; [email protected] 
 Department of Immunology, University of California Davis, Sacramento, CA 95616, USA; [email protected] 
 Department of Surgical Oncology, Roswell Park Comprehensive Cancer Center, Buffalo, NY 14203, USA; [email protected] 
10  Department of Thoracic Surgery, Roswell Park Comprehensive Cancer Center, Buffalo, NY 14203, USA; [email protected] 
11  Department of Medicine, Oklahoma University Health Stephenson Cancer Center, Oklahoma City, OK 73104, USA; [email protected] 
12  Department of Pharmacy, University of Kentucky College of Pharmacy, Lexington, KY 40506, USA; [email protected] 
13  Department of Cancer Biology, Moffitt Cancer Center, Tampa, FL 33612, USA; [email protected] 
14  Department of Medicine, Roswell Park Comprehensive Cancer Center, Buffalo, NY 14203, USA; [email protected] 
15  Precision Therapy and Diagnostics, Aster Insights, Hudson, FL 34667, USA; [email protected] 
16  Department of Immunology, Roswell Park Comprehensive Cancer Center, Buffalo, NY 14203, USA; [email protected] (B.D.); [email protected] (P.D.); [email protected] (P.K.); Department of Medicine, Roswell Park Comprehensive Cancer Center, Buffalo, NY 14203, USA; [email protected] 
First page
10847
Publication year
2023
Publication date
2023
Publisher
MDPI AG
ISSN
16616596
e-ISSN
14220067
Source type
Scholarly Journal
Language of publication
English
ProQuest document ID
2836436233
Copyright
© 2023 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/). Notwithstanding the ProQuest Terms and Conditions, you may use this content in accordance with the terms of the License.