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Subclone specific microenvironmental impact and drug response in refractory multiple myeloma revealed by single cell transcriptomics

ABSTRACT: Subclone specific microenvironmental impact and drug response in refractory multiple myeloma revealed by single cell transcriptomics

PROVIDER: PRJNA679548 | ENA |

REPOSITORIES: ENA

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Subclone specific microenvironmental impact and drug response in refractory multiple myeloma revealed by single cell transcriptomics

Project description:Virtually all patients with multiple myeloma become unresponsive to treatment over time. Relapsed/refractory multiple myeloma (RRMM) is accompanied by the clonal evolution of myeloma with heterogeneous genomic aberrations and profound changes of the bone marrow microenvironment (BME). However, the molecular mechanisms that drive drug resistance remain elusive. Here, we have analyzed the heterogeneous tumor cell population of 20 RRMM patients and its complex interaction network with the BME by single cell RNA-sequencing before/after treatment. Subclones with chromosome 1q-gain expressed a specific transcriptomic signature and frequently expanded during treatment. Furthermore, RRMM cells shaped an immune suppressive BME by upregulation of inflammatory cytokines and close interaction with the myeloid compartment. It was characterized by the accumulation of PD1+ γδ T-cells and tumor-associated macrophages as well as the depletion of hematopoietic progenitors. Thus, our study resolves transcriptional features of subclones in RRMM and mechanisms of microenvironmental reprogramming with implications for clinical decision-making.

2021-08-18 | GSE161801 | GEO

Subclone-specific microenvironmental impact and drug response in refractory multiple myeloma revealed by single-cell transcriptomics.

Project description: Not available

| S-EPMC8630108 | biostudies-literature

Resolving therapy resistance mechanisms in multiple myeloma by multiomics subclone analysis

Project description:Intratumor heterogeneity as a clinical challenge becomes most evident after several treatment lines, when multidrug-resistant subclones accumulate. To address this challenge, the characterization of resistance mechanisms at the subclonal level is key to identify common vulnerabilities. In this study, we integrate whole-genome sequencing, single-cell (sc) transcriptomics (scRNA sequencing), and chromatin accessibility (scATAC sequencing) together with mitochondrial DNA mutations to define subclonal architecture and evolution for longitudinal samples from 15 patients with relapsed or refractory multiple myeloma. We assess transcriptomic and epigenomic changes to resolve the multifactorial nature of therapy resistance and relate it to the parallel occurrence of different mechanisms: (1) preexisting epigenetic profiles of subclones associated with survival advantages, (2) converging phenotypic adaptation of genetically distinct subclones, and (3) subclone-specific interactions of myeloma and bone marrow microenvironment cells. Our study showcases how an integrative multiomics analysis can be applied to track and characterize distinct multidrug-resistant subclones over time for the identification of molecular targets against them.

2023-08-01 | GSE235783 | GEO

Single cell RNA sequencing of relapsed/refractory multiple myeloma

Project description:Most multiple myeloma patients develop refractory disease over time but the high tumor heterogeneity and complex interactions with the microenvironment make decisions on treatment challenging. Here, we have analyzed bone marrow aspirates of 20 relapsed/refractory multiple myeloma (RRMM) patients by single cell RNA-sequencing. We identify a transcriptional signature of the high-risk chromosome 1q gain and associated subclone dynamics over treatment. In the immune cell compartment, we observe an accumulation of exhausted gamma/delta T-cells and myeloid cells with immunosuppressive features. Via a co-expression analysis of receptor-ligand pairs we find that the underlying mechanisms include an upregulation of inflammatory cytokines and ligands of inhibitory receptors expressed on T and NK-cells. Finally, we identify microenvironmental changes that are specific for patients with 1q gain. Thus, our study resolves transcriptonal features of subclones in RRMM and mechanisms of microenvironmental reprogramming that can guide clinical decision making. Four WGS samples from hipo-K08K and hipo-067 were used as control.

| EGAS00001004805 | EGA

Altered Expression Profiles of tRNA-derived fragments in relapsed/refractory multiple myeloma

Project description:tRNA related fragments(tRF) and tRNA halves(tiRNA) are novel class of short non-coding RNA derived from tRNAs. Using RNA sequencing, we evaluated the tRFs/tiRNAs expression profiles in relapsed/refractory multiple myeloma and multiple myeloma patients. Bioinformatics analyses indicated that tRFs/tiRNAs may be involved in the progression and drug-resistance of multiple myeloma.

2021-05-19 | GSE171003 | GEO

Integrative Genomic and Transcriptomic Analyses of Refractory Multiple Myeloma

Project description:Integrative Genomic and Transcriptomic Analyses of Refractory Multiple Myeloma

| PRJNA746390 | ENA

Altered Expression Profiles of tRNA-derived fragments in relapsed/refractory multiple myeloma

Project description:Altered Expression Profiles of tRNA-derived fragments in relapsed/refractory multiple myeloma

| PRJNA718076 | ENA

The Spatio-Temporal Evolution of Multiple Myeloma from Baseline to Relapse-Refractory States

Project description:The Spatio-Temporal Evolution of Multiple Myeloma from Baseline to Relapse-Refractory States

| PRJNA768495 | ENA

The Spatio-Temporal Evolution of Multiple Myeloma from Baseline to Relapse-Refractory States

Project description:The Spatio-Temporal Evolution of Multiple Myeloma from Baseline to Relapse-Refractory States

| PRJNA768498 | ENA

Discovery of a drug targeting microenvironmental support for lymphoma cells by screening using patient-derived xenograft cells

Project description:Cell lines have been used for drug discovery as useful models of cancers; however, they do not recapitulate cancers faithfully, especially in the points of rapid growth rate and microenvironment independency. Consequently, the majority of conventional anti-cancer drugs are less sensitive to slow growing cells and do not target microenvironmental support, although most primary cancer cells grow slower than cell lines and depend on microenvironmental support. Here, we developed a novel high throughput drug screening system using patient-derived xenograft (PDX) cells of lymphoma that maintained primary cancer cell phenotype more than cell lines. The library containing 2613 known pharmacologically active substance and off-patent drugs were screened by this system. We could find many compounds showing higher cytotoxicity than conventional anti-tumor drugs. Especially, pyruvinium pamoate showed the highest activity, and its strong anti-tumor effect was confirmed also in vivo. We extensively investigated its mechanism of action and found that it inhibited glutathione supply from stromal cells to lymphoma cells, implying the importance of the stromal protection from ox 1 idative stress for lymphoma cell survival and a new therapeutic strategy for lymphoma. Our system introduces a primary cancer cell phenotype into cell-based phenotype screening and sheds new light on anti-cancer drug development. Global gene expression profiles of PDX cells showed high similarity to those of original primary cells. The correlation coefficient of gene expression profiles between PDX cells and the originalprimary cells was 0.814-0.890.

2015-08-31 | E-GEOD-71944 | biostudies-arrayexpress

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