Deciphering clonal evolution and dissemination of Multiple Myeloma cells in vivo
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ABSTRACT:
PROVIDER: PRJNA495356 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR7985760_1.fastq.gz | Fastqsanger.gz | |||
| SRR7985760_2.fastq.gz | Fastqsanger.gz | |||
| SRR7985770_1.fastq.gz | Fastqsanger.gz | |||
| SRR7985770_2.fastq.gz | Fastqsanger.gz | |||
| SRR7985780_1.fastq.gz | Fastqsanger.gz |
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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:This SuperSeries is composed of the following subset Series: GSE36822: Clonal competition with alternating dominance in multiple myeloma [244kCGH] GSE36823: Clonal competition with alternating dominance in multiple myeloma [44kCGH] GSE36824: Clonal competition with alternating dominance in multiple myeloma [GEP] Refer to individual Series
2012-03-27 | E-GEOD-36825 | biostudies-arrayexpress
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: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 multiple myeloma (MM), with most patients dying of relapsed disease. This multistage process requires tumor cells to enter the circulation, extravasate, and colonize distant bone marrow (BM) sites. Here, we developed a fluorescent or DNA-barcode clone-tracking system on MM PrEDiCT (progression through evolution and dissemination of clonal tumor cells) xenograft mouse model to study clonal behavior within the BM microenvironment. We showed that only the few clones that successfully adapt to the BM microenvironment can enter the circulation and colonize distant BM sites. RNA sequencing of primary and distant-site MM tumor cells revealed a progression signature sequentially activated along human MM progression and significantly associated with overall survival when evaluated against patient data sets. A total of 28 genes were then computationally predicted to be master regulators (MRs) of MM progression. HMGA1 and PA2G4 were validated in vivo using CRISPR-Cas9 in the PrEDiCT model and were shown to be significantly depleted in distant BM sites, indicating their role in MM progression and dissemination. Loss of HMGA1 and PA2G4 also compromised the proliferation, migration, and adhesion abilities of MM cells in vitro. Overall, our model successfully recapitulates key characteristics of human MM disease progression and identified potential new therapeutic targets for MM.
| S-EPMC8085483 | biostudies-literature
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:<h4><strong>BACKGROUND:</strong> Multiple myeloma is characterized by clonal proliferation of malignant plasma cells in the bone marrow that produce monoclonal immunoglobulins. N-glycosylation changes of these monoclonal immunoglobulins have been reported in multiple myeloma, but previous studies only detected limited serum N-glycan features.</h4><h4><strong>METHODS:</strong> Here, a more detailed study of the human serum N-glycome of 91 multiple myeloma patients and 51 controls was performed. We additionally analyzed sequential samples from patients (n = 7) which were obtained at different time points during disease development as well as 16 paired blood serum and bone marrow plasma samples. N-glycans were enzymatically released and measured by mass spectrometry after linkage specific derivatization of sialic acids.</h4><h4><strong>RESULTS:</strong> A decrease in both α2,3- and α2,6-sialylation, galactosylation and an increase in fucosylation within complex-type N-glycans were found in multiple myeloma patients compared to controls, as well as a decrease in difucosylation of diantennary glycans. The observed glycosylation changes were present in all ISS stages, including the 'low-risk' ISS I. In individual patients, difucosylation of diantennary glycans decreased with development of the disease. Protein N-glycosylation features from blood and bone marrow showed strong correlation. Moreover, associations of monoclonal immunoglobulin (M-protein) and albumin levels with glycan traits were discovered in multiple myeloma patients.</h4><h4><strong>CONCLUSIONS & GENERAL SIGNIFICANCE: </strong>In conclusion, serum protein N-glycosylation analysis could successfully distinguish multiple myeloma from healthy controls. Further studies are needed to assess the potential roles of glycan trait changes and the associations of glycans with clinical parameters in multiple myeloma early detection and prognosis.</h4>
2022-04-27 | MTBLS676 | MetaboLights
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:Copy number and Gene expression profiling multiple myeloma patients at multiple stages of their individual clinical course Identification of evolutionary paterns in multiple myeloma Copy number differences between individual CD138 purified tumor populations from multiple myeloma patients and control female using the Agilent 244A Human CGH microarray
2012-03-27 | E-GEOD-36822 | biostudies-arrayexpress