Myeloma-Modified Adipocytes Exhibit Metabolic Dysfunction and a Senescence-Associated Secretory Phenotype
Heather Fairfield, Maine Medical Center Research Institute, Scarborough, Maine.
Amel Dudakovic, Departments of Orthopedic Surgery and Biochemistry & Molecular Biology, Mayo Clinic, Rochester, Minnesota.
Casper M. Khatib, Department of Cellular and Molecular Medicine, Novo Nordisk Foundation Center for Stem Cell Biology (DanStem), University of Copenhagen, Copenhagen, Denmark.
Mariah Farrell, Maine Medical Center Research Institute, Scarborough, Maine.
Samantha Costa, Maine Medical Center Research Institute, Scarborough, Maine.
Carolyne Falank, Maine Medical Center Research Institute, Scarborough, Maine.
Maja Hinge, Division of Haematology, Department of Internal Medicine, Vejle Hospital, Vejle, Denmark.
Connor S. Murphy, Maine Medical Center Research Institute, Scarborough, Maine.
Victoria DeMambro, Maine Medical Center Research Institute, Scarborough, Maine.
Jessica A. Pettitt, The Garvan Institute of Medical Research, Sydney, New South Wales, Australia.
Christine W. Lary, Maine Medical Center Research Institute, Scarborough, Maine.
Heather E. Driscoll, Department of Biology, Norwich University, Northfield, Vermont.
Michelle M. McDonald, The Garvan Institute of Medical Research, Sydney, New South Wales, Australia.
Moustapha Kassem, Department of Cellular and Molecular Medicine, Novo Nordisk Foundation Center for Stem Cell Biology (DanStem), University of Copenhagen, Copenhagen, Denmark.
Clifford Rosen, Maine Medical Center Research Institute, Scarborough, Maine.
Thomas L. Andersen, Clinical Cell Biology, Department of Regional Health Research, Vejle/Lillebaelt Hospital, University of Southern Denmark, Vejle, Denmark.
Andre J. van Wijnen, Departments of Orthopedic Surgery and Biochemistry & Molecular Biology, Mayo Clinic, Rochester, Minnesota.
Abbas Jafari, Department of Cellular and Molecular Medicine, Novo Nordisk Foundation Center for Stem Cell Biology (DanStem), University of Copenhagen, Copenhagen, Denmark. mreagan@mmc.org ajafari@sund.ku.dk.
Michaela R. Reagan, Maine Medical Center Research Institute, Scarborough, Maine. mreagan@mmc.org ajafari@sund.ku.dk.
Abstract
Bone marrow adipocytes (BMAd) have recently been implicated in accelerating bone metastatic cancers, such as acute myelogenous leukemia and breast cancer. Importantly, bone marrow adipose tissue (BMAT) expands with aging and obesity, two key risk factors in multiple myeloma disease prevalence, suggesting that BMAds may influence and be influenced by myeloma cells in the marrow. Here, we provide evidence that reciprocal interactions and cross-regulation of myeloma cells and BMAds play a role in multiple myeloma pathogenesis and treatment response. Bone marrow biopsies from patients with multiple myeloma revealed significant loss of BMAT with myeloma cell infiltration of the marrow, whereas BMAT was restored after treatment for multiple myeloma. Myeloma cells reduced BMAT in different preclinical murine models of multiple myeloma and using myeloma cell-adipocyte cocultures. In addition, multiple myeloma cells altered adipocyte gene expression and cytokine secretory profiles, which were also associated with bioenergetic changes and induction of a senescent-like phenotype. , senescence markers were also increased in the bone marrow of tumor-burdened mice. BMAds, in turn, provided resistance to dexamethasone-induced cell-cycle arrest and apoptosis, illuminating a new possible driver of myeloma cell evolution in a drug-resistant clone. Our findings reveal that bidirectional interactions between BMAds and myeloma cells have significant implications for the pathogenesis and treatment of multiple myeloma. Targeting senescence in the BMAd or other bone marrow cells may represent a novel therapeutic approach for treatment of multiple myeloma. SIGNIFICANCE: This study changes the foundational understanding of how cancer cells hijack the bone marrow microenvironment and demonstrates that tumor cells induce senescence and metabolic changes in adipocytes, potentially driving new therapeutic directions.
