Obesity Is Associated with Altered Tumor Metabolism in Metastatic Melanoma-Reference-Cited by-同舟云学术

Obesity Is Associated with Altered Tumor Metabolism in Metastatic Melanoma

Published:2022-09-27 Issue:1 Volume:29 Page:154-164
ISSN:1078-0432
Container-title:Clinical Cancer Research
language:en
Short-container-title:

Author:

Hahn Andrew W.¹^ORCID,Menk Ashley V.²^ORCID,Rivadeneira Dayana B.²^ORCID,Augustin Ryan C.³^ORCID,Xu Mingchu⁴^ORCID,Li Jun⁵^ORCID,Wu Xiaogang⁴^ORCID,Mishra Aditya K.⁴^ORCID,Gide Tuba N.⁶^ORCID,Quek Camelia⁶^ORCID,Zang Yan²^ORCID,Spencer Christine N.⁷^ORCID,Menzies Alexander M.⁶^ORCID,Daniel Carrie R.⁸^ORCID,Hudgens Courtney W.⁹^ORCID,Nowicki Theodore¹⁰¹¹¹²^ORCID,Haydu Lauren E.¹³^ORCID,Khan M.A. Wadud¹³^ORCID,Gopalakrishnan Vancheswaran¹³^ORCID,Burton Elizabeth M.⁴^ORCID,Malke Jared¹³^ORCID,Simon Julie M.¹³^ORCID,Bernatchez Chantale¹⁴^ORCID,Putluri Nagireddy¹⁵^ORCID,Woodman Scott E.⁴^ORCID,Vashisht Gopal Y.N.¹⁶^ORCID,Guerrieri Renato¹⁶^ORCID,Fischer Grant M.¹⁷^ORCID,Wang Jian¹⁸^ORCID,Wani Khalida M.⁹^ORCID,Thompson John F.⁶^ORCID,Lee Jeffrey E.¹³^ORCID,Hwu Patrick¹⁹^ORCID,Ajami Nadim⁴^ORCID,Gershenwald Jeffrey E.¹²^ORCID,Long Georgina V.⁶²⁰²¹^ORCID,Scolyer Richard A.⁶²⁰²¹²²^ORCID,Tetzlaff Michael T.²³^ORCID,Lazar Alexander J.⁴⁹^ORCID,Schadendorf Dirk²⁴^ORCID,Wargo Jennifer A.⁴¹³^ORCID,Kirkwood John M.²⁵^ORCID,DeBerardinis Ralph J.²⁶^ORCID,Liang Han⁵^ORCID,Futreal Andrew⁴^ORCID,Zhang Jianhua⁴^ORCID,Wilmott James S.⁶^ORCID,Peng Weiyi²⁷^ORCID,Davies Michael A.¹⁶^ORCID,Delgoffe Greg M.²^ORCID,Najjar Yana G.²⁵^ORCID,McQuade Jennifer L.¹⁶^ORCID

Affiliation:

1. 1Division of Cancer Medicine, University of Texas MD Anderson Cancer Center, Houston, Texas.

2. 2Department of Immunology, University of Pittsburgh, Pittsburgh, Pennsylvania.

3. 3Department of Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania.

4. 4Department of Genomic Medicine, Division of Cancer Medicine, University of Texas MD Anderson Cancer Center, Houston, Texas.

5. 5Department of Bioinformatics and Computational Biology, Division of Basic Sciences, University of Texas MD Anderson Cancer Center, Houston, Texas.

6. 6Melanoma Institute of Australia, The University of Sydney, Sydney, New South Wales, Australia.

7. 7Parker Institute for Cancer Immunotherapy, San Francisco, California.

8. 8Department of Epidemiology, Division of Cancer Prevention and Population Sciences, University of Texas MD Anderson Cancer Center, Houston, Texas.

9. 9Department of Translational Molecular Pathology, Division of Pathology and Laboratory Medicine, University of Texas MD Anderson Cancer Center, Houston, Texas.

10. 10Division of Pediatric Hematology-Oncology, Department of Pediatrics, University of California Los Angeles, Los Angeles, California.

11. 11Jonsson Comprehensive Cancer Center, University of California Los Angeles, Los Angeles, California.

12. 12Eli and Edythe Broad Center for Regenerative Medicine and Stem Cell Research, University of California Los Angeles, Los Angeles, California.

13. 13Department of Surgical Oncology, Division of Surgery, University of Texas MD Anderson Cancer Center, Houston, Texas.

14. 14Department of Biologics Development, Division of Therapeutics Discovery, University of Texas MD Anderson Cancer Center, Houston, Texas.

15. 15Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, Texas.

16. 16Department of Melanoma Medical Oncology, Division of Cancer Medicine, University of Texas MD Anderson Cancer Center, Houston, Texas.

17. 17Department of Pathology, Brigham and Women's Hospital, Boston, Massachusetts.

18. 18Department of Biostatistics, Division of Biosciences, University of Texas MD Anderson Cancer Center, Houston, Texas.

19. 19Department of Cutaneous Oncology, Moffitt Cancer Center, Tampa Bay, Florida.

20. 20Faculty of Medicine and Health, The University of Sydney, Sydney, New South Wales, Australia.

21. 21Charles Perkins Centre, The University of Sydney, Sydney, New South Wales, Australia.

22. 22Tissue Pathology and Diagnostic Oncology, Royal Prince Alfred Hospital and NSW Health Pathology, Sydney, New South Wales, Australia.

23. 23Division of Dermatopathology, Department of Pathology, University of California San Francisco, San Francisco, California.

24. 24Department of Dermatology, Venereology, and Allergology, University Hospital Essen and German Cancer Consortium, Partner site Essen, Germany.

25. 25Division of Hematology/Oncology, Department of Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania.

26. 26Children's Medical Research Institute and Howard Hughes Medical Institute, University of Texas Southwestern Medical Center, Dallas, Texas.

27. 27Department of Biology and Biochemistry, University of Houston, Houston, Texas.

Abstract

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. See related commentary by Smalley, p. 5

Funder

Conquer Cancer Foundation

Transdisciplinary Research in Energetics and Cancer Research Training Workshop

MD Anderson Cancer Center for Energy Balance in Cancer Prevention and Survivorship

Melanoma Research Alliance

Elkins Foundation

Seerave Foundation

Rising Tide Foundation

Mark Foundation For Cancer Research

MD Anderson Cancer Center Moonshot Program

Prostate Cancer Foundation

Howard Hughes Medical Institute