Myeloma-Modified Adipocytes Exhibit Metabolic Dysfunction and a Senescence-Associated Secretory Phenotype
Document Type
Article
Publication Date
2-1-2021
Institution/Department
Oncology
Journal Title
Cancer research
MeSH Headings
3T3 Cells; Adipocytes (metabolism, pathology, physiology); Adipose Tissue (pathology); Aging (pathology); Animals; Antineoplastic Agents, Hormonal (pharmacology); Apoptosis (drug effects); Biopsy; Bone Marrow (drug effects, pathology); Bone Marrow Cells (pathology); Cell Communication (physiology); Cell Cycle (drug effects); Cellular Senescence; Coculture Techniques; Cohort Studies; Cytokines (metabolism); Dexamethasone (pharmacology); Disease Progression; Drug Resistance, Neoplasm; Female; Gene Expression; Humans; Mice; Mice, Inbred C57BL; Mice, SCID; Multiple Myeloma (drug therapy, etiology, pathology); Obesity (pathology); Phenotype
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.
First Page
634
Last Page
647
Recommended Citation
Fairfield H, Dudakovic A, Khatib CM, et al. Myeloma-Modified Adipocytes Exhibit Metabolic Dysfunction and a Senescence-Associated Secretory Phenotype. Cancer Res. 2021;81(3):634-647. doi:10.1158/0008-5472.CAN-20-1088