Obesogenic High-Fat Diet and MYC Cooperate to Promote Lactate Accumulation and Tumor Microenvironment Remodeling in Prostate Cancer-Reference-Cited by-同舟云学术

Obesogenic High-Fat Diet and MYC Cooperate to Promote Lactate Accumulation and Tumor Microenvironment Remodeling in Prostate Cancer

Published:2024-06-04 Issue:11 Volume:84 Page:1834-1855
ISSN:0008-5472
Container-title:Cancer Research
language:en
Short-container-title:

Author:

Boufaied Nadia¹^ORCID,Chetta Paolo²³^ORCID,Hallal Tarek¹⁴^ORCID,Cacciatore Stefano⁵^ORCID,Lalli Daniela⁶^ORCID,Luthold Carole⁷^ORCID,Homsy Kevin⁷^ORCID,Imada Eddie L.⁸^ORCID,Syamala Sudeepa⁹^ORCID,Photopoulos Cornelia⁹^ORCID,Di Matteo Anna¹⁰^ORCID,de Polo Anna¹^ORCID,Storaci Alessandra Maria¹¹^ORCID,Huang Ying⁹^ORCID,Giunchi Francesca¹²^ORCID,Sheridan Patricia A.¹³^ORCID,Michelotti Gregory¹³^ORCID,Nguyen Quang-De¹⁴^ORCID,Zhao Xin¹⁵^ORCID,Liu Yang¹⁵^ORCID,Davicioni Elai¹⁵^ORCID,Spratt Daniel E.¹⁶^ORCID,Sabbioneda Simone¹⁰^ORCID,Maga Giovanni¹⁰^ORCID,Mucci Lorelei A.¹⁷^ORCID,Ghigna Claudia¹⁰^ORCID,Marchionni Luigi⁸^ORCID,Butler Lisa M.¹⁸^ORCID,Ellis Leigh¹⁹^ORCID,Bordeleau François⁷²⁰^ORCID,Loda Massimo⁸^ORCID,Vaira Valentina¹¹²¹^ORCID,Labbé David P.¹⁴²²^ORCID,Zadra Giorgia⁹¹⁰²³^ORCID

Affiliation:

1. 1Cancer Research Program, Research Institute of the McGill University Health Centre, Montréal, Québec, Canada.

2. 2University of Milan, Residency Program in Pathology, Milan, Italy.

3. 3Department of Pathology, Massachusetts General Hospital, Boston, Massachusetts.

4. 4Department of Anatomy and Cell Biology, McGill University, Montréal, Québec, Canada.

5. 5Bionformatics Unit, International Centre for Genetic Engineering and Biotechnology (ICGEB), Cape Town, South Africa.

6. 6Department of Science and Technological Innovation, University of Piemonte Orientale “A. Avogadro,” Alessandria, Italy.

7. 7CHU de Québec-Université Laval Research Center (Oncology Division) and Cancer Research Center, Centre de Recherche en Organogénèse Expérimentale/LOEX, Université Laval, Québec, Canada.

8. 8Department of Pathology and Laboratory Medicine, Weill Cornell Medicine, New York Presbyterian-Weill Cornell Campus, New York, New York.

9. 9Department of Oncologic Pathology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts.

10. 10Institute of Molecular Genetics, National Research Council (CNR-IGM), Pavia, Italy.

11. 11Department of Pathophysiology and Transplantation, University of Milan, Milan, Italy.

12. 12Pathology Unit, IRCCS Azienda Ospedaliero-Universitaria di Bologna, Bologna, Italy.

13. 13Metabolon Inc., Morrisville, North Carolina.

14. 14Department of Imaging, Lurie Family Imaging Center, Center for Biomedical Imaging in Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts.

15. 15Veracyte, South San Francisco, California.

16. 16Department of Radiation Oncology, University Hospitals Seidman Cancer Center, Case Western Reserve University School of Medicine, Cleveland, Ohio.

17. 17Department of Epidemiology, Harvard T.H. Chan School of Public Health, Boston, Massachusetts.

18. 18South Australian Immunogenomics Cancer Institute and Freemasons Centre for Male Health and Wellbeing, University of Adelaide, South Australian Health and Medical Research Institute, Adelaide, Australia.

19. 19Department of Surgery, Center for Prostate Disease Research, Murtha Cancer Center Research Program, Uniformed Services University of the Health Sciences and the Walter Reed National Military Medical Center; The Henry M. Jackson Foundation for the Advancement of Military Medicine, Inc., Bethesda, Maryland.

20. 20Department of Molecular Biology, Clinical Biochemistry, and Pathology, Laval University, Québec, Canada.

21. 21Division of Pathology, Fondazione IRCCS Ca’ Granda Ospedale Maggiore Policlinico, Milan, Italy.

22. 22Division of Urology, Department of Surgery, McGill University, Montréal, Québec, Canada.

23. 23Department of Pathology, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts.

Abstract

Abstract Cancer cells exhibit metabolic plasticity to meet oncogene-driven dependencies while coping with nutrient availability. A better understanding of how systemic metabolism impacts the accumulation of metabolites that reprogram the tumor microenvironment (TME) and drive cancer could facilitate development of precision nutrition approaches. Using the Hi-MYC prostate cancer mouse model, we demonstrated that an obesogenic high-fat diet (HFD) rich in saturated fats accelerates the development of c-MYC–driven invasive prostate cancer through metabolic rewiring. Although c-MYC modulated key metabolic pathways, interaction with an obesogenic HFD was necessary to induce glycolysis and lactate accumulation in tumors. These metabolic changes were associated with augmented infiltration of CD206+ and PD-L1+ tumor-associated macrophages (TAM) and FOXP3+ regulatory T cells, as well as with the activation of transcriptional programs linked to disease progression and therapy resistance. Lactate itself also stimulated neoangiogenesis and prostate cancer cell migration, which were significantly reduced following treatment with the lactate dehydrogenase inhibitor FX11. In patients with prostate cancer, high saturated fat intake and increased body mass index were associated with tumor glycolytic features that promote the infiltration of M2-like TAMs. Finally, upregulation of lactate dehydrogenase, indicative of a lactagenic phenotype, was associated with a shorter time to biochemical recurrence in independent clinical cohorts. This work identifies cooperation between genetic drivers and systemic metabolism to hijack the TME and promote prostate cancer progression through oncometabolite accumulation. This sets the stage for the assessment of lactate as a prognostic biomarker and supports strategies of dietary intervention and direct lactagenesis blockade in treating advanced prostate cancer. Significance: Lactate accumulation driven by high-fat diet and MYC reprograms the tumor microenvironment and promotes prostate cancer progression, supporting the potential of lactate as a biomarker and therapeutic target in prostate cancer. See related commentary by Frigo, p. 1742

Funder

AIRC Foundation for Cancer Research

Canadian Institutes of Health Research

Dana-Farber Cancer Institute

U.S. Department of Defense

World Cancer Research Fund International

Publisher

American Association for Cancer Research (AACR)

Link

https://aacrjournals.org/cancerres/article-pdf/84/11/1834/3472409/1834.pdf

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