Epigenetic Reprogramming of Cancer-Associated Fibroblasts Deregulates Glucose Metabolism and Facilitates Progression of Breast Cancer
Lisa M. Becker,
Joyce T. O’Connell,
Annie P. Vo,
Margo P. Cain,
Desiree Tampe,
Lauren Bizarro,
Hikaru Sugimoto,
Anna K. McGow,
John M. Asara,
Sara Lovisa,
Kathleen M. McAndrews,
Rafal Zielinski,
Philip L. Lorenzi,
Michael Zeisberg,
Sughra Raza,
Valerie S. LeBleu,
Raghu Kalluri
Affiliations
Lisa M. Becker
Department of Cancer Biology, Metastasis Research Center, University of Texas MD Anderson Cancer Center, Houston, TX 77054, USA
Joyce T. O’Connell
Division of Matrix Biology, Department of Medicine, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, MA 02215, USA
Annie P. Vo
Division of Matrix Biology, Department of Medicine, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, MA 02215, USA
Margo P. Cain
Department of Cancer Biology, Metastasis Research Center, University of Texas MD Anderson Cancer Center, Houston, TX 77054, USA
Desiree Tampe
Department of Nephrology and Rheumatology, Göttingen University Medical Center, Georg August University, Göttingen 37075, Germany
Lauren Bizarro
Department of Cancer Biology, Metastasis Research Center, University of Texas MD Anderson Cancer Center, Houston, TX 77054, USA; Division of Matrix Biology, Department of Medicine, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, MA 02215, USA
Hikaru Sugimoto
Department of Cancer Biology, Metastasis Research Center, University of Texas MD Anderson Cancer Center, Houston, TX 77054, USA; Division of Matrix Biology, Department of Medicine, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, MA 02215, USA
Anna K. McGow
Department of Radiology, Brigham and Women’s Hospital, Boston, MA 02215, USA
John M. Asara
Division of Signal Transduction, Beth Israel Deaconess Medical Center, Boston, MA 02215, USA; Department of Medicine, Harvard Medical School, Boston, MA 02215, USA
Sara Lovisa
Department of Cancer Biology, Metastasis Research Center, University of Texas MD Anderson Cancer Center, Houston, TX 77054, USA
Kathleen M. McAndrews
Department of Cancer Biology, Metastasis Research Center, University of Texas MD Anderson Cancer Center, Houston, TX 77054, USA
Rafal Zielinski
Department of Experimental Therapeutics, University of Texas MD Anderson Cancer Center, Houston, TX 77054, USA
Philip L. Lorenzi
Metabolomics Core Facility, Department of Bioinformatics & Computational Biology, University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA
Michael Zeisberg
Department of Nephrology and Rheumatology, Göttingen University Medical Center, Georg August University, Göttingen 37075, Germany
Sughra Raza
Department of Radiology, Brigham and Women’s Hospital, Boston, MA 02215, USA
Valerie S. LeBleu
Department of Cancer Biology, Metastasis Research Center, University of Texas MD Anderson Cancer Center, Houston, TX 77054, USA; Division of Matrix Biology, Department of Medicine, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, MA 02215, USA; Feinberg School of Medicine, Northwestern University, Chicago, IL 60611, USA; Corresponding author
Raghu Kalluri
Department of Cancer Biology, Metastasis Research Center, University of Texas MD Anderson Cancer Center, Houston, TX 77054, USA; Division of Matrix Biology, Department of Medicine, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, MA 02215, USA; Department of Bioengineering, Rice University, Houston, TX 77030, USA; Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, TX 77030, USA; Corresponding author
Summary: The mechanistic contributions of cancer-associated fibroblasts (CAFs) in breast cancer progression remain to be fully understood. While altered glucose metabolism in CAFs could fuel cancer cells, how such metabolic reprogramming emerges and is sustained needs further investigation. Studying fibroblasts isolated from patients with benign breast tissues and breast cancer, in conjunction with multiple animal models, we demonstrate that CAFs exhibit a metabolic shift toward lactate and pyruvate production and fuel biosynthetic pathways of cancer cells. The depletion or suppression of the lactate production of CAFs alter the tumor metabolic profile and impede tumor growth. The glycolytic phenotype of the CAFs is in part sustained through epigenetic reprogramming of HIF-1α and glycolytic enzymes. Hypoxia induces epigenetic reprogramming of normal fibroblasts, resulting in a pro-glycolytic, CAF-like transcriptome. Our findings suggest that the glucose metabolism of CAFs evolves during tumor progression, and their breast cancer-promoting phenotype is partly mediated by oxygen-dependent epigenetic modifications.
