Multiple Myeloma Cells Alter Adipogenesis, Increase Senescence-Related and Inflammatory Gene Transcript Expression, and Alter Metabolism in Preadipocytes

Abstract

Within the bone marrow microenvironment, mesenchymal stromal cells (MSCs) are an essential precursor to bone marrow adipocytes and osteoblasts. The balance between this progenitor pool and mature cells (adipocytes and osteoblasts) is often skewed by disease and aging. In multiple myeloma (MM), a cancer of the plasma cell that predominantly grows within the bone marrow, as well as other cancers, MSCs, preadipocytes, and adipocytes have been shown to directly support tumor cell survival and proliferation. Increasing evidence supports the idea that MM-associated MSCs are distinct from healthy MSCs, and their gene expression profiles may be predictive of myeloma patient outcomes. Here we directly investigate how MM cells affect the differentiation capacity and gene expression profiles of preadipocytes and bone marrow MSCs. Our studies reveal that MM.1S cells cause a marked decrease in lipid accumulation in differentiating 3T3-L1 cells. Also, MM.1S cells or MM.1S-conditioned media altered gene expression profiles of both 3T3-L1 and mouse bone marrow MSCs. 3T3-L1 cells exposed to MM.1S cells before adipogenic differentiation displayed gene expression changes leading to significantly altered pathways involved in steroid biosynthesis, the cell cycle, and metabolism (oxidative phosphorylation and glycolysis) after adipogenesis. MM.1S cells induced a marked increase in 3T3-L1 expression of MM-supportive genes including Il-6 and Cxcl12 (SDF1), which was confirmed in mouse MSCs by qRT-PCR, suggesting a forward-feedback mechanism. In vitro experiments revealed that indirect MM exposure prior to differentiation drives a senescent-like phenotype in differentiating MSCs, and this trend was confirmed in MM-associated MSCs compared to MSCs from normal donors. In direct co-culture, human mesenchymal stem cells (hMSCs) exposed to MM.1S, RPMI-8226, and OPM-2 prior to and during differentiation, exhibited different levels of lipid accumulation as well as secreted cytokines. Combined, our results suggest that MM cells can inhibit adipogenic differentiation while stimulating expression of the senescence associated secretory phenotype (SASP) and other pro-myeloma molecules. This study provides insight into a novel way in which MM cells manipulate their microenvironment by altering the expression of supportive cytokines and skewing the cellular diversity of the marrow.

Diverse breast adipose stromal cell biology in women at high risk for developing breast cancer

“…IL-6, TGFβ) that may in uence the local breast microenvironment in a manner that contributes to cancer progression. Age, obesity and cancer have been shown to be drivers of senescence and/or an adipogenesis defect in ASCs [19][20][21][22]. In the current study, we observed a senescent bASC phenotype in both pre-menopausal (patients D, F, and H) and post-menopausal (patients, C, E, and G) women.…”

Metabolic Disorders in Multiple Myeloma

“…Myeloma cells may regulate adipogenesis in order to sustain their survival and homing in the bone marrow milieu [ 118 ]. Myeloma cells induce the expression of genes related to an inflammatory state and a senescence associated secretory phenotype (SAPS) in the adipocytes, in order to promote myelomatogenesis and myeloma cell survival [ 119 ]. Interestingly, the response to treatment may restore the adipocyte homeostasis in the bone marrow [ 120 ].…”

Report From the 6th International Meeting on Bone Marrow Adiposity (BMA2020)

“…Dr. Podgorski concluded her talk by stressing an importance of understanding the role of BMAT in tumor adaptation and survival in bone, as a tool to reveal novel, mechanistic targets for therapies for prostate and breast bone-metastatic diseases, which continue to be incurable (27). After this, Emma Morris discussed the effects of PPARg agonist BAGDE on myeloma cells and bone marrow adipocytes (28), Sonia Severin showed a functional link between marrow adipocytes and the development of megakaryocytes (29), and Mariah Farrell revealed that bone marrow adipocytes support multiple myeloma drug resistance and induce adipocyte mimicry, increasing cell survival (30,31). Overall, this session stressed an importance of understanding the role of BMAT in hematopoiesis and cancer cell survival in bone, while underscoring a prominent role of adipocytes in the regulation of different components of hematopoietic niche.…”