Dataset Information

S100A8/S100A9 Promote Progression of Multiple Myeloma via Expansion of Megakaryocytes.

ABSTRACT: Multiple myeloma is characterized by clonal proliferation of plasma cells that accumulate preferentially in the bone marrow (BM). The tumor microenvironment is one of the leading factors that promote tumor progression. Neutrophils and monocytes are a major part of the BM tumor microenvironment, but the mechanism of their contribution to multiple myeloma progression remains unclear. Here, we describe a novel mechanism by which S100A8/S100A9 proteins produced by BM neutrophils and monocytes promote the expansion of megakaryocytes supporting multiple myeloma progression. S100A8/S100A9 alone was not sufficient to drive megakaryopoiesis but markedly enhanced the effect of thrombopoietin, an effect that was mediated by Toll-like receptor 4 and activation of the STAT5 transcription factor. Targeting S100A9 with tasquinimod as a single agent and in combination with lenalidomide and with proteasome inhibitors has potent antimyeloma effect that is at least partly independent of the adaptive immune system. This newly identified axis of signaling involving myeloid cells and megakaryocytes may provide a new avenue for therapeutic targeting in multiple myeloma.

Significance

We identified a novel mechanism by which myeloid cells promote myeloma progression independently of the adaptive immune system. Specifically, we discovered a novel role of S100A8/S100A9, the most abundant proteins produced by neutrophils and monocytes, in regulation of myeloma progression via promotion of the megakaryocyte expansion and angiogenesis. Tasquinimod, an inhibitor of S100A9, has potent antimyeloma effects as a single agent and in combination with lenalidomide and with proteasome inhibitors.

SUBMITTER: Lin C

PROVIDER: S-EPMC10010194 | biostudies-literature | 2023 Mar

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

S100A8/S100A9 Promote Progression of Multiple Myeloma via Expansion of Megakaryocytes.

Lin Cindy C Garcia-Gerique Laura L Bonner Erin E EE Mastio Jerome J Rosenwasser Matthew M Cruz Zachary Z Lawler Michael M Bernabei Luca L Muthumani Kar K Liu Qin Q Poncz Mortimer M Vogl Thomas T Törngren Marie M Eriksson Helena H Vogl Dan T DT Gabrilovich Dmitry I DI Nefedova Yulia Y

Cancer research communications 20230313 3

Multiple myeloma is characterized by clonal proliferation of plasma cells that accumulate preferentially in the bone marrow (BM). The tumor microenvironment is one of the leading factors that promote tumor progression. Neutrophils and monocytes are a major part of the BM tumor microenvironment, but the mechanism of their contribution to multiple myeloma progression remains unclear. Here, we describe a novel mechanism by which S100A8/S100A9 proteins produced by BM neutrophils and monocytes promot ...[more]

PMID: 36923707

Similar Datasets

Project description:BackgroundMultiple myeloma (MM) is a hematologic malignancy characterized by the clonal proliferation of plasma cells, with extramedullary myeloma (EMM) being an aggressive form involving malignant infiltration beyond the bone marrow. Copper metabolism is essential for tumor proliferation and metastasis, with copper metabolism MURR1 domain (COMMD) proteins regulating these processes and maintaining copper homeostasis. Dysregulated copper homeostasis contributes to cancer progression, including MM, with elevated copper levels linked to disease aggressiveness and poor prognosis. This study investigates the role of the COMMD3 in mediating MM cell progression, particularly its influence on copper metabolism.MethodsComprehensive bioinformatics analyses were conducted on bone marrow and extramedullary samples to determine the expression of COMMD3, which was validated through in vitro and in vivo functional assays. The MM cell lines RPMI8226 and MM1S underwent lentiviral transfection for COMMD3 overexpression and knockdown. RNA sequencing was conducted on COMMD3 knockdown cells to identify differentially expressed genes. Functional assays measured cell proliferation, migration, apoptosis, and copper metabolism, with a non-obese diabetic severe combined immune-deficiency gamma (NSG) mouse xenograft model providing in vivo validation.ResultsElevated COMMD3 expression was correlated with extramedullary myeloma and poor prognosis in MM patients. COMMD3 promoted MM cell proliferation and migration, modulating intracellular copper levels, likely through the ATOX1-ATP7A-LOX copper-metabolism-related pathway. High ATOX1 expression was correlated with worse outcomes, and ATOX1 inhibition abolished COMMD3's effects.ConclusionsThis study highlights the pivotal role of COMMD3 in MM progression, particularly via the ATOX1-ATP7A-LOX axis. These findings provide insights into EMM mechanisms and position COMMD3 as a potential therapeutic target. Future research is needed to validate these findings in larger clinical cohorts and to unravel the precise molecular interactions between COMMD3 and copper metabolism proteins.

Project description:IntroductionThe objective was to evaluate the changes in S100A8 S100A9, and their complex (S100A8/S100A9) in cartilage during the onset of osteoarthritis (OA) as opposed to inflammatory arthritis.MethodsS100A8 and S100A9 protein localization were determined in antigen-induced inflammatory arthritis in mice, mouse femoral head cartilage explants stimulated with interleukin-1 (IL-1), and in surgically-induced OA in mice. Microarray expression profiling of all S100 proteins in cartilage was evaluated at different times after initiation of degradation in femoral head explant cultures stimulated with IL-1 and surgically-induced OA. The effect of S100A8, S100A9 or the complex on the expression of aggrecan (Acan), collagen II (Col2a1), disintegrin and metalloproteases with thrombospondin motifs (Adamts1, Adamts 4 &Adamts 5), matrix metalloproteases (Mmp1, Mmp3, Mmp13 &Mmp14) and tissue inhibitors of metalloproteinases (Timp1, Timp2 &Timp3), by primary adult ovine articular chondrocytes was determined using real time quantitative reverse transcription polymerase chain reaction (qRT-PCR).ResultsStimulation with IL-1 increased chondrocyte S100a8 and S100a9 mRNA and protein levels. There was increased chondrocyte mRNA expression of S100a8 and S100a9 in early but not late mouse OA. However, loss of the S100A8 staining in chondrocytes occurred as mouse OA progressed, in contrast to the positive reactivity for both S100A8 and S100A9 in chondrocytes in inflammatory arthritis in mice. Homodimeric S100A8 and S100A9, but not the heterodimeric complex, significantly upregulated chondrocyte Adamts1, Adamts4 and Adamts 5, Mmp1, Mmp3 and Mmp13 gene expression, while collagen II and aggrecan mRNAs were significantly decreased.ConclusionsChondrocyte derived S100A8 and S100A9 may have a sustained role in cartilage degradation in inflammatory arthritis. In contrast, while these proteins may have a role in initiating early cartilage degradation in OA by upregulating MMPs and aggrecanases, their reduced expression in late stages of OA suggests they do not have an ongoing role in cartilage degradation in this non-inflammatory arthropathy.

Dataset Information

S100A8/S100A9 Promote Progression of Multiple Myeloma via Expansion of Megakaryocytes.

Significance

Publications

S100A8/S100A9 Promote Progression of Multiple Myeloma via Expansion of Megakaryocytes.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets