Obesity is associated with altered tumor metabolism in metastatic melanoma.

Hahn AW, Menk AV, Rivadeneira DB, Augustin RC, Xu M, Li J, Wu X, Mishra AK, Gide TN, Quek C, Zang Y, Spencer CN, Menzies AM, Daniel CR, Hudgens CW, Nowicki T, Haydu LE, Khan MAW, Gopalakrishnan V, Burton EM, Malke J, Simon JM, Bernatchez C, Putluri N, Woodman SE, Gopal Y N V, Guerrieri R, Fischer GM, Wang J, Wani KM, Thompson JF, Lee JE, Hwu P, Ajami N, Gershenwald JE, Long GV, Scolyer RA, Tetzlaff MT, Lazar AJ, Schadendorf D, Wargo JA, Kirkwood JM, DeBerardinis RJ, Liang H, Futreal A, Zhang J, Wilmott JS, Peng W, Davies MA, Delgoffe GM, Najjar YG, McQuade JL. Clin Cancer Res. 2022 Sep 27:CCR-22-2661. doi: 10.1158/1078-0432.CCR-22-2661. Epub ahead of print. PMID: 36166093.

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.

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