Obesity Is Associated with Altered Tumor Metabolism in Metastatic Melanoma

Andrew W. Hahn, Ashley V. Menk, Dayana B. Rivadeneira, Ryan C. Augustin, Mingchu Xu, Jun Li, Xiaogang Wu, Aditya K. Mishra, Tuba N. Gide, Camelia Quek, Yan Zang, Christine N. Spencer, Alexander M. Menzies, Carrie R. Daniel, Courtney W. Hudgens, Theodore Nowicki, Lauren E. Haydu, M. A.Wadud Khan, Vancheswaran Gopalakrishnan, Elizabeth M. BurtonJared Malke, Julie M. Simon, Chantale Bernatchez, Nagireddy Putluri, Scott E. Woodman, Y. N.Vashisht Gopal, Renato Guerrieri, Grant M. Fischer, Jian Wang, Khalida M. Wani, John F. Thompson, Jeffrey E. Lee, Patrick Hwu, Nadim Ajami, Jeffrey E. Gershenwald, Georgina V. Long, Richard A. Scolyer, Michael T. Tetzlaff, Alexander J. Lazar, Dirk Schadendorf, Jennifer A. Wargo, John M. Kirkwood, Ralph J. DeBerardinis, Han Liang, Andrew Futreal, Jianhua Zhang, James S. Wilmott, Weiyi Peng, Michael A. Davies, Greg M. Delgoffe, Yana G. Najjar, Jennifer L. McQuade

Research output: Contribution to journalArticlepeer-review

8 Scopus citations

Abstract

Purpose: Overweight/obese (OW/OB) patients with metastatic melanoma unexpectedly have improved outcomes with immune checkpoint inhibitors (ICI) and BRAF-targeted therapies. The mechanism(s) underlying this association remain unclear, thus we assessed the integrated molecular, metabolic, and immune profile of tumors, as well as gut microbiome features, for associations with patient body mass index (BMI). Experimental Design: Associations between BMI [normal (NL < 25) or OW/OB (BMI ≥ 25)] and tumor or microbiome characteristics were examined in specimens from 782 patients with metastatic melanoma across 7 cohorts. DNA associations were evaluated in The Cancer Genome Atlas cohort. RNA sequencing from 4 cohorts (n = 357) was batch corrected and gene set enrichment analysis (GSEA) by BMI category was performed. Metabolic profiling was conducted in a subset of patients (x = 36) by LC/MS, and in flow-sorted melanoma tumor cells (x = 37) and patient-derived melanoma cell lines (x = 17) using the Seahorse XF assay. Gut microbiome features were examined in an independent cohort (n = 371). Results: DNA mutations and copy number variations were not associated with BMI. GSEA demonstrated that tumors from OW/ OB patients were metabolically quiescent, with downregulation of oxidative phosphorylation and multiple other metabolic pathways. Direct metabolite analysis and functional metabolic profiling confirmed decreased central carbon metabolism in OW/OB metastatic melanoma tumors and patient-derived cell lines. The overall structure, diversity, and taxonomy of the fecal microbiome did not differ by BMI. Conclusions: These findings suggest that the host metabolic phenotype influences melanoma metabolism and provide insight into the improved outcomes observed in OW/OB patients with metastatic melanoma treated with ICIs and targeted therapies.

Original languageEnglish (US)
Pages (from-to)154-164
Number of pages11
JournalClinical Cancer Research
Volume29
Issue number1
DOIs
StatePublished - Jan 1 2023

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

MD Anderson CCSG core facilities

  • Functional Proteomics Reverse Phase Protein Array Core
  • Bioinformatics Shared Resource
  • Metabolomics Facility

Fingerprint

Dive into the research topics of 'Obesity Is Associated with Altered Tumor Metabolism in Metastatic Melanoma'. Together they form a unique fingerprint.

Cite this