Metabolic Dysregulation Explains the Diverse Impacts of Obesity in Males and Females with Gastrointestinal Cancers.
| Title: | Metabolic Dysregulation Explains the Diverse Impacts of Obesity in Males and Females with Gastrointestinal Cancers. |
|---|---|
| Authors: | Rosario SR; Department of Biostatistics and Bioinformatics, Roswell Park Comprehensive Cancer Center, Buffalo, NY 14203, USA.; Department of Pharmacology and Therapeutics, Roswell Park Comprehensive Cancer Center, Buffalo, NY 14203, USA.; Dong B; Department of Immunology, Roswell Park Comprehensive Cancer Center, Buffalo, NY 14203, USA.; Zhang Y; Department of Biostatistics and Bioinformatics, Roswell Park Comprehensive Cancer Center, Buffalo, NY 14203, USA.; Hsiao HH; Department of Biostatistics and Bioinformatics, Roswell Park Comprehensive Cancer Center, Buffalo, NY 14203, USA.; Isenhart E; Department of Biostatistics and Bioinformatics, Roswell Park Comprehensive Cancer Center, Buffalo, NY 14203, USA.; Wang J; Department of Biostatistics and Bioinformatics, Roswell Park Comprehensive Cancer Center, Buffalo, NY 14203, USA.; Siegel EM; Department of Cancer Epidemiology, H. Lee Moffitt Cancer Center, Tampa, FL 33612, USA.; Monjazeb AM; Department of Radiation Oncology, University of California Davis, Sacramento, CA 95616, USA.; Owen DH; Department of Medical Oncology, Ohio State University Comprehensive Cancer Center, Columbus, OH 43210, USA.; Dey P; Department of Immunology, Roswell Park Comprehensive Cancer Center, Buffalo, NY 14203, USA.; Tabung FK; Department of Epidemiology, Ohio State University Comprehensive Cancer Center, Columbus, OH 43210, USA.; Spakowicz DJ; Department of Medical Oncology, Ohio State University Comprehensive Cancer Center, Columbus, OH 43210, USA.; Murphy WJ; Department of Immunology, University of California Davis, Sacramento, CA 95616, USA.; Edge S; Department of Surgical Oncology, Roswell Park Comprehensive Cancer Center, Buffalo, NY 14203, USA.; Yendamuri S; Department of Thoracic Surgery, Roswell Park Comprehensive Cancer Center, Buffalo, NY 14203, USA.; Ibrahimi S; Department of Medicine, Oklahoma University Health Stephenson Cancer Center, Oklahoma City, OK 73104, USA.; Kolesar JM; Department of Pharmacy, University of Kentucky College of Pharmacy, Lexington, KY 40506, USA.; McDonald PH; Department of Cancer Biology, Moffitt Cancer Center, Tampa, FL 33612, USA.; Vadehra D; Department of Medicine, Roswell Park Comprehensive Cancer Center, Buffalo, NY 14203, USA.; Churchman M; Precision Therapy and Diagnostics, Aster Insights, Hudson, FL 34667, USA.; Liu S; Department of Biostatistics and Bioinformatics, Roswell Park Comprehensive Cancer Center, Buffalo, NY 14203, USA.; Kalinski P; Department of Immunology, Roswell Park Comprehensive Cancer Center, Buffalo, NY 14203, USA.; Mukherjee S; Department of Immunology, Roswell Park Comprehensive Cancer Center, Buffalo, NY 14203, USA.; Department of Medicine, Roswell Park Comprehensive Cancer Center, Buffalo, NY 14203, USA. |
| Source: | International journal of molecular sciences [Int J Mol Sci] 2023 Jun 29; Vol. 24 (13). Date of Electronic Publication: 2023 Jun 29. |
| Publication Type: | Journal Article |
| Language: | English |
| Journal Info: | Publisher: MDPI Country of Publication: Switzerland NLM ID: 101092791 Publication Model: Electronic Cited Medium: Internet ISSN: 1422-0067 (Electronic) Linking ISSN: 14220067 NLM ISO Abbreviation: Int J Mol Sci Subsets: MEDLINE |
| Imprint Name(s): | Original Publication: Basel, Switzerland : MDPI, [2000- |
| MeSH Terms: | Gastrointestinal Neoplasms*/genetics ; Adenocarcinoma*; Obesity/genetics ; Male ; Female ; Humans ; Kynurenine ; Tryptophan ; Leukocytes, Mononuclear |
| 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. |
| References: | Methods Mol Biol. 2009;563:219-39. (PMID: 19597788); Semin Cancer Biol. 2022 Nov;86(Pt 3):542-565. (PMID: 35151845); Cancer Metab. 2022 Oct 26;10(1):17. (PMID: 36289552); SAGE Open Med. 2020 Apr 28;8:2050312120918265. (PMID: 32435480); Lancet. 2014 Aug 30;384(9945):766-81. (PMID: 24880830); Ann Acad Med Singap. 2009 Jan;38(1):57-9. (PMID: 19221672); Nat Med. 2019 Jan;25(1):141-151. (PMID: 30420753); Nat Commun. 2018 Dec 14;9(1):5330. (PMID: 30552315); Endocr Relat Cancer. 2011 Jun 08;18(3):371-84. (PMID: 21490239); Front Endocrinol (Lausanne). 2011 Sep 27;2:32. (PMID: 22654802); Am J Clin Nutr. 2014 May;99(5):999-1005. (PMID: 24572565); J Hematol Oncol. 2021 Nov 6;14(1):187. (PMID: 34742349); JAMA. 2003 Jan 1;289(1):76-9. (PMID: 12503980); Cell. 2020 Dec 23;183(7):1848-1866.e26. (PMID: 33301708); Front Oncol. 2020 Dec 09;10:607909. (PMID: 33363037); Cell. 2010 Apr 2;141(1):39-51. (PMID: 20371344); Adv Nutr. 2012 Jul 01;3(4):491-8. (PMID: 22797984); J Immunother Cancer. 2019 Mar 29;7(1):89. (PMID: 30922394); Int J Obes (Lond). 2016 Dec;40(12):1817-1822. (PMID: 27686524); Biochim Biophys Acta. 2010 Mar;1801(3):246-51. (PMID: 19818872); Front Immunol. 2016 Jan 05;6:637. (PMID: 26779183); Genome Biol. 2014;15(12):550. (PMID: 25516281); Bioinformatics. 2011 Jun 15;27(12):1739-40. (PMID: 21546393); Biol Sex Differ. 2020 Jul 23;11(1):43. (PMID: 32703269); Nat Rev Drug Discov. 2022 Feb;21(2):141-162. (PMID: 34862480); BMC Obes. 2016 Apr 29;3:22. (PMID: 27148454); Nucleic Acids Res. 2015 Apr 20;43(7):e47. (PMID: 25605792); Int J Obes (Lond). 2008 Sep;32(9):1431-7. (PMID: 18607383); N Engl J Med. 2016 Aug 25;375(8):794-8. (PMID: 27557308); Cold Spring Harb Mol Case Stud. 2015 Oct;1(1):a000588. (PMID: 27148576); Cancers (Basel). 2022 Apr 06;14(7):. (PMID: 35406621); Front Immunol. 2019 Aug 14;10:1940. (PMID: 31475003); Gut. 2018 Oct;67(10):1855-1863. (PMID: 28754779); Lancet Oncol. 2018 Mar;19(3):310-322. (PMID: 29449192); Nucleic Acids Res. 2018 Jan 4;46(D1):D661-D667. (PMID: 29136241); Molecules. 2019 Sep 04;24(18):. (PMID: 31487832); Front Genet. 2016 Sep 20;7:168. (PMID: 27703473) |
| Grant Information: | R01 CA240751 United States CA NCI NIH HHS |
| Contributed Indexing: | Keywords: cancer; gender disparity; immunity; metabolism; obesity; omics |
| Substance Nomenclature: | 343-65-7 (Kynurenine); 8DUH1N11BX (Tryptophan) |
| Entry Date(s): | Date Created: 20230714 Date Completed: 20230717 Latest Revision: 20240127 |
| Update Code: | 20260130 |
| PubMed Central ID: | PMC10342094 |
| DOI: | 10.3390/ijms241310847 |
| PMID: | 37446025 |
| Database: | MEDLINE |
Journal Article