Metabolic Dysregulation Explains the Diverse Impacts of Obesity in Males and Females with Gastrointestinal Cancers

Spencer R. Rosario; Bowen Dong; Yali Zhang; Hua Hsin Hsiao; Emily Isenhart; Jianmin Wang; Erin M. Siegel; Arta M. Monjazeb; Dwight H. Owen; Prasenjit Dey; Fred K. Tabung; Daniel J. Spakowicz; William J. Murphy; Stephen Edge; Sai Yendamuri; Sami Ibrahimi; Jill M. Kolesar; Patsy H. McDonald; Deepak Vadehra; Michelle Churchman; Song Liu; Pawel Kalinski; Sarbajit Mukherjee

doi:10.3390/ijms241310847

Metabolic Dysregulation Explains the Diverse Impacts of Obesity in Males and Females with Gastrointestinal Cancers

Spencer R. Rosario, Bowen Dong, Yali Zhang, Hua Hsin Hsiao, Emily Isenhart, Jianmin Wang, Erin M. Siegel, Arta M. Monjazeb, Dwight H. Owen, Prasenjit Dey, Fred K. Tabung, Daniel J. Spakowicz, William J. Murphy, Stephen Edge, Sai Yendamuri, Sami Ibrahimi, Jill M. Kolesar, Patsy H. McDonald, Deepak Vadehra, Michelle ChurchmanSong Liu, Pawel Kalinski, Sarbajit Mukherjee

Research output: Contribution to journal › Article › peer-review

2 Scopus citations

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.

Original language	English
Article number	10847
Journal	International Journal of Molecular Sciences
Volume	24
Issue number	13
DOIs	https://doi.org/10.3390/ijms241310847
State	Published - Jul 2023

Bibliographical note

Publisher Copyright:
© 2023 by the authors.

Funding

We would like to thank staff scientists Krystin Mantione, M.S., and Sarah Burke at the Roswell Park Comprehensive Cancer Center (RP) Bioanalytics, Metabolomics and Pharmacokinetics (BMPK) Shared Resource for guidance and assistance with our metabolomics studies. We thank Prashant Singh and his research associates in the RP Genomics Shared Resource (GSR) for performing RNA-sequencing. We would also like to thank the RP Flow Cytometry Shared Resource. This work was supported by the IOTN: Data Management and Resource-Sharing Center (U24CA232979, S.R.R.), ARTNet: Coordinating and Data Management Center (U24CA274159, S.R.R.), and the TREC Fellowship Training Workshop (R25CA203650 (PI: Melinda Irwin); S.R.R.). The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health. Computational resources were maintained by the Center for Computational Research at the University at Buffalo.

Funders	Funder number
Data Management and Resource-Sharing Center	U24CA232979, U24CA274159
Harvard Transdisciplinary Research in Energetics and Cancer Center, Harvard University	R25CA203650

Keywords

cancer
gender disparity
immunity
metabolism
obesity
omics

ASJC Scopus subject areas

Catalysis
Molecular Biology
Spectroscopy
Computer Science Applications
Physical and Theoretical Chemistry
Organic Chemistry
Inorganic Chemistry

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

Access to Document

10.3390/ijms241310847

Cite this

Rosario, S. R., Dong, B., Zhang, Y., Hsiao, H. H., Isenhart, E., Wang, J., Siegel, E. M., Monjazeb, A. M., Owen, D. H., Dey, P., Tabung, F. K., Spakowicz, D. J., Murphy, W. J., Edge, S., Yendamuri, S., Ibrahimi, S., Kolesar, J. M., McDonald, P. H., Vadehra, D., ... Mukherjee, S. (2023). Metabolic Dysregulation Explains the Diverse Impacts of Obesity in Males and Females with Gastrointestinal Cancers. International Journal of Molecular Sciences, 24(13), Article 10847. https://doi.org/10.3390/ijms241310847

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title = "Metabolic Dysregulation Explains the Diverse Impacts of Obesity in Males and Females with Gastrointestinal Cancers",

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.",

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author = "Rosario, {Spencer R.} and Bowen Dong and Yali Zhang and Hsiao, {Hua Hsin} and Emily Isenhart and Jianmin Wang and Siegel, {Erin M.} and Monjazeb, {Arta M.} and Owen, {Dwight H.} and Prasenjit Dey and Tabung, {Fred K.} and Spakowicz, {Daniel J.} and Murphy, {William J.} and Stephen Edge and Sai Yendamuri and Sami Ibrahimi and Kolesar, {Jill M.} and McDonald, {Patsy H.} and Deepak Vadehra and Michelle Churchman and Song Liu and Pawel Kalinski and Sarbajit Mukherjee",

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Rosario, SR, Dong, B, Zhang, Y, Hsiao, HH, Isenhart, E, Wang, J, Siegel, EM, Monjazeb, AM, Owen, DH, Dey, P, Tabung, FK, Spakowicz, DJ, Murphy, WJ, Edge, S, Yendamuri, S, Ibrahimi, S, Kolesar, JM, McDonald, PH, Vadehra, D, Churchman, M, Liu, S, Kalinski, P & Mukherjee, S 2023, 'Metabolic Dysregulation Explains the Diverse Impacts of Obesity in Males and Females with Gastrointestinal Cancers', International Journal of Molecular Sciences, vol. 24, no. 13, 10847. https://doi.org/10.3390/ijms241310847

TY - JOUR

T1 - Metabolic Dysregulation Explains the Diverse Impacts of Obesity in Males and Females with Gastrointestinal Cancers

AU - Rosario, Spencer R.

AU - Dong, Bowen

AU - Zhang, Yali

AU - Hsiao, Hua Hsin

AU - Isenhart, Emily

AU - Wang, Jianmin

AU - Siegel, Erin M.

AU - Monjazeb, Arta M.

AU - Owen, Dwight H.

AU - Dey, Prasenjit

AU - Tabung, Fred K.

AU - Spakowicz, Daniel J.

AU - Murphy, William J.

AU - Edge, Stephen

AU - Yendamuri, Sai

AU - Ibrahimi, Sami

AU - Kolesar, Jill M.

AU - McDonald, Patsy H.

AU - Vadehra, Deepak

AU - Churchman, Michelle

AU - Liu, Song

AU - Kalinski, Pawel

AU - Mukherjee, Sarbajit

PY - 2023/7

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N2 - 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.

AB - 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.

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Metabolic Dysregulation Explains the Diverse Impacts of Obesity in Males and Females with Gastrointestinal Cancers

Abstract

Bibliographical note

Funding

Keywords

ASJC Scopus subject areas

UN SDGs

Access to Document

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