TY  - JOUR
AU  - Hahn, Andrew W
AU  - Menk, Ashley V
AU  - Rivadeneira, Dayana B
AU  - Augustin, Ryan C
AU  - Xu, Mingchu
AU  - Li, Jun
AU  - Wu, Xiaogang
AU  - Mishra, Aditya K
AU  - Gide, Tuba N
AU  - Quek, Camelia
AU  - Zang, Yan
AU  - Spencer, Christine N
AU  - Menzies, Alexander M
AU  - Daniel, Carrie R
AU  - Hudgens, Courtney W
AU  - Nowicki, Theodore
AU  - Haydu, Lauren E
AU  - Khan, M A Wadud
AU  - Gopalakrishnan, Vancheswaran
AU  - Burton, Elizabeth M
AU  - Malke, Jared
AU  - Simon, Julie M
AU  - Bernatchez, Chantale
AU  - Putluri, Nagireddy
AU  - Woodman, Scott E
AU  - Vashisht Gopal, Y. N.
AU  - Guerrieri, Renato
AU  - Fischer, Grant M
AU  - Wang, Jian
AU  - Wani, Khalida M
AU  - Thompson, John F
AU  - Lee, Jeffrey E
AU  - Hwu, Patrick
AU  - Ajami, Nadim
AU  - Gershenwald, Jeffrey E
AU  - Long, Georgina V
AU  - Scolyer, Richard A
AU  - Tetzlaff, Michael T
AU  - Lazar, Alexander J
AU  - Schadendorf, Dirk
AU  - Wargo, Jennifer A
AU  - Kirkwood, John M
AU  - DeBerardinis, Ralph J
AU  - Liang, Han
AU  - Futreal, Andrew
AU  - Zhang, Jianhua
AU  - Wilmott, James S
AU  - Peng, Weiyi
AU  - Davies, Michael A
AU  - Delgoffe, Greg M
AU  - Najjar, Yana G
AU  - McQuade, Jennifer L
TI  - Obesity Is Associated with Altered Tumor Metabolism in Metastatic Melanoma.
JO  - Clinical cancer research
VL  - 29
IS  - 1
SN  - 1078-0432
CY  - Philadelphia, Pa. [u.a.]
PB  - AACR
M1  - DKFZ-2023-00034
SP  - 154 - 164
PY  - 2023
AB  - 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).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).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.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. See related commentary by Smalley, p. 5.
KW  - Humans
KW  - Risk Factors
KW  - DNA Copy Number Variations
KW  - Obesity: complications
KW  - Overweight
KW  - Melanoma: genetics
KW  - Melanoma: complications
KW  - Body Mass Index
KW  - Neoplasms, Second Primary
LB  - PUB:(DE-HGF)16
C6  - pmid:36166093
DO  - DOI:10.1158/1078-0432.CCR-22-2661
UR  - https://inrepo02.dkfz.de/record/186665
ER  -