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ROBO1 Promotes Homing, Dissemination, and Survival of Multiple Myeloma within the Bone Marrow Microenvironment.

ABSTRACT: The bone marrow (BM) microenvironment actively promotes multiple myeloma (MM) pathogenesis and therapies targeting both cancer cells and the niche are highly effective. We were interested in identifying novel signaling pathways supporting MM-BM crosstalk. Mutations in the transmembrane receptor Roundabout 1 (ROBO1) were recently identified in MM patients, however their functional consequences are uncertain. Through protein structure-function studies, we discovered that ROBO1 is necessary for MM adhesion to BM stromal and endothelial cells and ROBO1 knock out (KO) compromises BM homing and engraftment in a disseminated mouse model. ROBO1 KO significantly decreases MM proliferation in vitro and intra- and extramedullary tumor growth, in vivo. Mechanistically, ROBO1 C-terminus is cleaved in a ligand-independent fashion and is sufficient to promote MM proliferation. Viceversa, mutants lacking the cytoplasmic domain, including the human-derived G674* truncation, act dominantly negative. Interactomic and RNA sequencing studies suggest ROBO1 may be involved in RNA processing, supporting further studies.

SUBMITTER: Bianchi G

PROVIDER: S-EPMC8265993 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:Multiple myeloma (MM) is a lethal B cell neoplasm characterized by clonal expansion of malignant plasma cells in the bone marrow and remains incurable due to disease relapse and drug resistance. Bone marrow adipocytes (BMAs) are emerging as playing active functions that can support myeloma cell growth and survival. The aim of this study is to investigate myeloma-mesenchymal stem cells (MSCs) interaction and the impact of such interactions on the pathogenesis of MM using in vitro co-culture assay. Here we provide evidence that MM cell up-regulated MSCs to express PPAR-γ and pushes MSCs differentiation toward adipocytes at the expense of osteoblasts in co-culture manner. The increased BMAs can effectively enhance MM cell to proliferation, migration, and chemoresistance via cell-cell contact and/or cytokines release regulated by PPAR-γ signal pathway. This effect was partially reversed in medium containing PPAR-γ antagonist G3335 and indicated that G3335 distorts the maturation of MSC-derived adipocytes and cytokines release by adipocytes through inhibition of PPAR-γ, a key transcriptional factor for the activation of adipogenesis, or cell to cell contact, or both. In meantime, we observed higher expression of adipocyte differentiation associated genes DLK1, DGAT1, FABP4, and FASN both in MSCs and MSC derived adipocytes, but the osteoblast differentiation-associated gene ALP was down regulated in MSCs. These finding mean that direct consequence of MM/MSC interaction that play a role in MM pathogenesis. Consistent with those in vitro results, our primary clinical observation also showed that bone marrow samples from MM patients had significantly higher bone adiposity in comparison with controls and the number of adipocytes decreased in those who were response to anti-MM therapy. Our finding suggested that BMAs may have an important contribution to MM progression, particularly in drugs resistant of MM cells, and plays an important contribution in MM bone disease and treatment failure, but more clinical studies are needed to confirm its role.

Project description:BackgroundThe PD-1/PD-L1 axis has recently emerged as an immune checkpoint that controls antitumor immune responses also in hematological malignancies. However, the use of anti-PD-L1/PD-1 antibodies in multiple myeloma (MM) patients still remains debated, at least in part because of discordant literature data on PD-L1/PD-1 expression by MM cells and bone marrow (BM) microenvironment cells. The unmet need to identify patients which could benefit from this therapeutic approach prompts us to evaluate the BM expression profile of PD-L1/PD-1 axis across the different stages of the monoclonal gammopathies.MethodsThe PD-L1/PD-1 axis was evaluated by flow cytometry in the BM samples of a total cohort of 141 patients with monoclonal gammopathies including 24 patients with Monoclonal Gammopathy of Undetermined Significance (MGUS), 38 patients with smoldering MM (SMM), and 79 patients with active MM, including either newly diagnosed or relapsed-refractory patients. Then, data were correlated with the main immunological and clinical features of the patients.ResultsFirst, we did not find any significant difference between MM and SMM patients in terms of PD-L1/PD-1 expression, on both BM myeloid (CD14+) and lymphoid subsets. On the other hand, PD-L1 expression by CD138+ MM cells was higher in both SMM and MM as compared to MGUS patients. Second, the analysis on the total cohort of MM and SMM patients revealed that PD-L1 is expressed at higher level in CD14+CD16+ non-classical monocytes compared with classical CD14+CD16- cells, independently from the stage of disease. Moreover, PD-L1 expression on CD14+ cells was inversely correlated with BM serum levels of the anti-tumoral cytokine, IL-27. Interestingly, relapsed MM patients showed an inverted CD4+/CD8+ ratio along with high levels of pro-tumoral IL-6 and a positive correlation between %CD14+PD-L1+ and %CD8+PD-1+ cells as compared to both SMM and newly diagnosed MM patients suggesting a highly compromised immune-compartment with low amount of CD4+ effector cells.ConclusionsOur data indicate that SMM and active MM patients share a similar PD-L1/PD-1 BM immune profile, suggesting that SMM patients could be an interesting target for PD-L1/PD-1 inhibition therapy, in light of their less compromised and more responsive immune-compartment.

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ROBO1 Promotes Homing, Dissemination, and Survival of Multiple Myeloma within the Bone Marrow Microenvironment.

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