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

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.

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.

Cancer research. 2024 Jun 04 [Epub]

Nadia Boufaied, Paolo Chetta, Tarek Hallal, Stefano Cacciatore, Daniela Lalli, Carole Luthold, Kevin Homsy, Eddie L Imada, Sudeepa Syamala, Cornelia Photopoulos, Anna Di Matteo, Anna de Polo, Alessandra Maria Storaci, Ying Huang, Francesca Giunchi, Patricia A Sheridan, Gregory Michelotti, Quang-De Nguyen, Xin Zhao, Yang Liu, Elai Davicioni, Daniel E Spratt, Simone Sabbioneda, Giovanni Maga, Lorelei A Mucci, Claudia Ghigna, Luigi Marchionni, Lisa M Butler, Leigh Ellis, François Bordeleau, Massimo Loda, Valentina Vaira, David P Labbé, Giorgia Zadra

Cancer Research Program, Research Institute of the McGill University Health Centre, Montréal, Québec, Canada., University of Milan, Residency Program in Pathology, Milan, Italy., Bionformatics Unit, International Centre for Genetic Engineering and Biotechnology (ICGEB), Cape Town, South Africa., Department of Science and Technological Innovation, University of Piemonte Orientale "A. Avogadro," Alessandria, Italy., CHU de Québec-Université Laval Research Center (Oncology Division) and Cancer Research Center, Centre de Recherche en Organogénèse Expérimentale/LOEX, Université Laval, Québec, Canada., Department of Pathology and Laboratory Medicine, Weill Cornell Medicine, New York Presbyterian-Weill Cornell Campus, New York, New York., Department of Oncologic Pathology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts., Institute of Molecular Genetics, National Research Council (CNR-IGM), Pavia, Italy., Department of Pathophysiology and Transplantation, University of Milan, Milan, Italy., Pathology Unit, IRCCS Azienda Ospedaliero-Universitaria di Bologna, Bologna, Italy., Metabolon Inc., Morrisville, North Carolina., Department of Imaging, Lurie Family Imaging Center, Center for Biomedical Imaging in Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts., Veracyte, South San Francisco, California., Department of Radiation Oncology, University Hospitals Seidman Cancer Center, Case Western Reserve University School of Medicine, Cleveland, Ohio., Department of Epidemiology, Harvard T.H. Chan School of Public Health, Boston, Massachusetts., South Australian Immunogenomics Cancer Institute and Freemasons Centre for Male Health and Wellbeing, University of Adelaide, South Australian Health and Medical Research Institute, Adelaide, Australia., Department 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.