Tissue-resident macrophages promote multiple myeloma early dissemination and progression via IL-6 and TNFa
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ABSTRACT:
PROVIDER: PRJNA736048 | ENA |
REPOSITORIES: ENA
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Project description:Multiple myeloma (MM) is a plasma cell malignancy characterized by the presence of multiple foci in the skeleton. These distinct tumor foci indicate cycles of tumor growth and dissemination that seed new clusters and drives disease progression. Utilizing an intra-tibial Vk*MYC murine myeloma, we found that CD169 + radiation-resistant, tissue-resident macrophages (MPs) were critical for myeloma early dissemination and disease progression. While depletion of these MPs had no effect on tumor proliferation, it reduced myeloma BM egress and spreading to other bones, which improved overall survival as a single therapy and in combination with BM transplantation. Myeloma dissemination correlated with an increased inflammatory signature in BM MPs, as well as production of IL-6 and TNFα by tumor-associated MPs (TAMs). Exogenous i.v. IL-6 and TNFa could trigger myeloma intravasation in the BM by increasing vascular leakiness in the BM, and by enhancing myeloma motility by reducing CD138 adhesion. Moreover, mice lacking IL-6 had defects in myeloma dissemination as in MP-depleted recipients. While in TNFa or TNFaR deficient mice had defects in MM dissemination, engraftment was also impaired. These effects on myeloma dissemination required production of cytokines in the radiation-resistant compartment, containing these radiation-resistant BM MPs. Taken together, we propose BM egress of myeloma cells is regulated by localized inflammation in foci, driven in part by CD169 + MPs.
2021-06-09 | GSE176385 | GEO
Project description:Multiple myeloma involves early dissemination of malignant plasma cells across the bone marrow; however, the initial steps of dissemination remain unclear. Human bone marrow-derived mesenchymal stromal cells (hMSCs) stimulate myeloma cell expansion (e.g., IL-6) and simultaneously retain myeloma cells via chemokines (e.g., CXCL12) and adhesion factors. Hence, we hypothesized that the imbalance between cell division and retention drives dissemination. We present an in vitro model using primary hMSCs co-cultured with INA-6 myeloma cells. Time-lapse microscopy revealed proliferation and attachment/detachment dynamics. Separation techniques (V-well adhesion assay and well plate sandwich centrifugation) were established to isolate MSC-interacting myeloma subpopulations that were characterized by RNAseq, cell viability and apoptosis. Results were correlated with gene expression data (n=837) and survival of myeloma patients (n=536). On dispersed hMSCs, INA-6 saturate hMSC-surface before proliferating into large homotypic aggregates, from which single cells detached completely. On confluent hMSCs, aggregates were replaced by strong heterotypic hMSC-INA-6 interactions, which modulated apoptosis time-dependently. Only INA-6 daughter cells (nMA-INA6) detached from hMSCs by cell division but sustained adherence to hMSC-adhering mother cells (MA-INA6). Isolated nMA-INA6 indicated hMSC-autonomy through superior viability after IL6 withdrawal and upregulation of proliferation-related genes. MA-INA6 upregulated adhesion and retention factors (CXCL12), that, intriguingly, were highly expressed in myeloma samples from patients with longer overall and progression-free survival, but their expression decreased in relapsed myeloma samples. Altogether, in vitro dissemination of INA-6 is driven by detaching daughter cells after a cycle of hMSC-(re)attachment and proliferation, involving adhesion factors that represent a bone marrow-retentive phenotype with potential clinical relevance.
2024-04-11 | GSE261423 | GEO
Project description:Deciphering clonal evolution and dissemination of Multiple Myeloma cells in vivo
| PRJNA495356 | ENA
Project description:The number of peripheral blood (PB) circulating tumor cells (CTCs) predicts risk of transformation in smoldering multiple myeloma (MM) and survival in active MM. Growing evidence suggests that as the tumor progresses and the microenvironment becomes hypoxic, clonal plasma cells (PCs) constantly invade new regions of the bone marrow (BM) through induced systemic recirculation. Of note, the frequency of CTCs is typically low and thus, it could be hypothesized that the dissemination of MM is made by few tumor cells with unique features that induce them to egress the BM and spread the disease through PB. This hypothesis has not been demonstrated because the molecular profile of CTCs in MM has not been investigated. We used gene expression profiling (GEP) arrays to identify gene regulatory networks related to disease dissemination by comparing the molecular profile of CTCs with patient-matched BM clonal PCs.
2019-02-26 | GSE124436 | GEO
Project description:The number of peripheral blood (PB) circulating tumor cells (CTCs) predicts risk of transformation in smoldering multiple myeloma (MM) and survival in active MM. Growing evidence suggests that as the tumor progresses and the microenvironment becomes hypoxic, clonal plasma cells (PCs) constantly invade new regions of the bone marrow (BM) through induced systemic recirculation. Of note, the frequency of CTCs is typically low and thus, it could be hypothesized that the dissemination of MM is made by few tumor cells with unique features that induce them to egress the BM and spread the disease through PB. This hypothesis has not been demonstrated because the molecular profile of CTCs in MM has not been investigated. We used gene expression profiling (GEP) arrays to identify gene regulatory networks related to disease dissemination by comparing the molecular profile of CTCs with patient-matched BM clonal PCs.
2019-02-26 | GSE124435 | GEO
Project description:Clonal evolution drives tumor progression, dissemination and relapse in cancer, and dissemination or metastasis of the tumor cells from primary site to other organs is the leading cause of death for cancer patients. This multi-stage process requires tumor cells to survive in the circulation, extravasate at distant sites, then colonization. The whole process involves contributions from both the tumor cells and microenvironment. Here we developed and applied a clonal tracking ‘rainbow’ system into a tumor dissemination xenograft mouse model (SCID-mu) to study the clonal behaviors with the presence of a bone marrow environment showing that only a few subclones successfully remodeled by BM environment can exit the primary site and further colonize in distant tissues. RNA-sequencing results of primary and disseminated MM tumor cells revealed a metastatic signature, which is sequentially activated during human MM progression and significantly associated with overall survival when evaluated against a public patient dataset suggesting SCID-mu model characterizes MM dissemination phenotypically and mechanistically.
2018-10-10 | GSE121007 | GEO
Project description:The number of peripheral blood (PB) circulating tumor cells (CTCs) predicts risk of transformation in smoldering multiple myeloma (MM) and survival in active MM. Growing evidence suggests that as the tumor progresses and the microenvironment becomes hypoxic, clonal plasma cells (PCs) constantly invade new regions of the bone marrow (BM) through induced systemic recirculation. Of note, the frequency of CTCs is typically low and thus, it could be hypothesized that the dissemination of MM is made by few tumor cells with unique features that induce them to egress the BM and spread the disease through PB. This hypothesis has not been demonstrated because the molecular profile of CTCs in MM has not been investigated.
2019-02-26 | GSE124437 | GEO
Project description:Treatment with IL-1b or TNFa enhance the proliferation of alveolar type 2 cells in organoid culture. Here, we examine the downstream mechanisms that enhance AEC2 proliferation after IL-1b and TNFa treatments, we performed RNA-seq analysis of AEC2s isolated from organoids 6 hrs after exposure to either cytokine. We identified 165 differentially expressed genes that were common in both IL-1b and TNFa treated AEC2s compared to saline treated controls.
2019-04-01 | GSE125662 | GEO
Project description:TNFa stimulated human cultured podocytes compared with unstimulated (vehicle control (VC)) podocytes. Incubation of podocytes with high concentrations of TNF alpha led to an overexpression of ICAM1 in particular. We studied this system as a comparator for organoids also stimulated with the same concentration of TNFa. Four conditions (6 replicates each) 1) treatment (5 ng/mL TNFa) for 24 hours 2) control (PBS) for 24h 3) treatment (5 ng/mL TNFa) for 48 hours 4) control (PBS) for 48h
2023-05-19 | PXD032130 | Pride
Project description:TNFa stimulated human cultured podocytes compared with unstimulated (vehicle control (VC)) podocytes. Incubation of podocytes with high concentrations of TNF alpha led to an overexpression of ICAM1 in particular. We studied this system as a comparator for organoids also stimulated with the same concentration of TNFa. Four conditions (6 replicates each) 1) treatment (5 ng/mL TNFa) for 24 hours 2) control (PBS) for 24h 3) treatment (5 ng/mL TNFa) for 48 hours 4) control (PBS) for 48h
2023-05-19 | PXD032107 | Pride