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Dynamic transcriptional reprogramming leads to novel immunotherapeutic vulnerabilities in myeloma

ABSTRACT: Dynamic transcriptional reprogramming leads to novel immunotherapeutic vulnerabilities in myeloma

PROVIDER: PRJNA681554 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	SRR13194609_1.fastq.gz	Fastqsanger.gz
	SRR13194609_2.fastq.gz	Fastqsanger.gz
	SRR13167118_1.fastq.gz	Fastqsanger.gz
	SRR13167118_2.fastq.gz	Fastqsanger.gz
	SRR13167119_1.fastq.gz	Fastqsanger.gz

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Dynamic transcriptional reprogramming leads to immunotherapeutic vulnerabilities in myeloma.

Project description:While there is extensive evidence for genetic variation as a basis for treatment resistance, other sources of variation result from cellular plasticity. Using multiple myeloma as an example of an incurable lymphoid malignancy, we show how cancer cells modulate lineage restriction, adapt their enhancer usage and employ cell-intrinsic diversity for survival and treatment escape. By using single-cell transcriptome and chromatin accessibility profiling, we show that distinct transcriptional states co-exist in individual cancer cells and that differential transcriptional regulon usage and enhancer rewiring underlie these alternative transcriptional states. We demonstrate that exposure to standard treatment further promotes transcriptional reprogramming and differential enhancer recruitment while simultaneously reducing developmental potential. Importantly, treatment generates a distinct complement of actionable immunotherapy targets, such as CXCR4, which can be exploited to overcome treatment resistance. Our studies therefore delineate how to transform the cellular plasticity that underlies drug resistance into immuno-oncologic therapeutic opportunities.

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Dynamic transcriptional reprogramming leads to novel immunotherapeutic vulnerabilities in myeloma

Project description:While there is extensive evidence for genetic variation as a basis for treatment resistance, other sources of variation result from cellular plasticity. Using multiple myeloma as an example of an incurable lymphoid malignancy, we show how cancer cells modulate lineage restriction, adapt their enhancer usage and employ cell-intrinsic diversity for survival and treatment escape. By using single cell transcriptome and chromatin accessibility profiling, we show that distinct transcriptional states co-exist in individual cancer cells and that differential transcriptional regulon usage and enhancer rewiring underlie these alternate transcriptional states. We demonstrate that exposure to standard treatment further promotes transcriptional reprogramming and differential enhancer recruitment, while simultaneously reducing developmental potential. Importantly, treatment generates a novel complement of actionable immunotherapy targets, such as CXCR4, which can be exploited to overcome treatment resistance. Our studies therefore delineate how to transform the cellular plasticity that underlies drug resistance into novel immuno-oncologic therapeutic opportunities.

2021-08-25 | GSE162337 | GEO

Project description:Dynamic transcriptional reprogramming leads to novel immunotherapeutic vulnerabilities in myeloma

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Pan-HDAC Inhibition Reverses the Warburg Effect and Leads to Metabolic Vulnerabilities

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CDK7 controls E2F- and MYC-driven proliferative and metabolic vulnerabilities in multiple myeloma

Project description:CDK7 controls E2F- and MYC-driven proliferative and metabolic vulnerabilities in multiple myeloma

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Defining the cell surface proteomic landscape of multiple myeloma reveals immunotherapeutic strategies and biomarkers of drug resistance

Project description:Defining the cell surface proteomic landscape of multiple myeloma reveals immunotherapeutic strategies and biomarkers of drug resistance

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CD86 regulates a pro-survival signal in myeloma cells

Project description:While multiple myeloma patient prognosis has improved over the past decade, research towards discovery of new therapeutic avenues is important, and could lead to a cure for this chronic plasma cell malignancy. Data analysis from a myeloma patient database shows that the CD28-CD86 signaling module may provide a survival advantage in myeloma cells that negatively impacts patient outcome. Here we show that blocking the CD28-CD86 pathway, by silencing or with CTLA-4-Ig, leads to myeloma cell death. Blockade of this pathway leads to downregulation of nutrient transporters, integrins, and IRF4, a known myeloma survival factor. Our data also indicate that CD86, the canonical "ligand" in this pathway, is mediating a pro-survival signal via the cytosolic domain that has not been previously described. These findings indicate that blockade of this pathway is a promising therapeutic avenue for myeloma, as it leads to modulation of different processes important in cell viability.

2017-01-01 | GSE89511 | GEO

Defining the cell surface proteomic landscape of multiple myeloma reveals immunotherapeutic strategies and biomarkers of drug resistance

Project description:The myeloma cell surface proteome (“surfaceome”) not only determines tumor interaction with the microenvironment but serves as an emerging arena for therapeutic development. Here, we use glycoprotein capture proteomics to first define surface markers most-enriched on myeloma when compared to B-cell malignancy models, revealing unexpected biological signatures unique to malignant plasma cells. We next integrate our proteomic dataset with existing transcriptome databases, nominating CCR10 and TXNDC11 as possible monotherapeutic targets and CD48 as a promising co-target for increasing avidity of BCMA-directed cellular therapies. We further identify potential biomarkers of resistance to proteasome inhibitors and lenalidomide including changes in CD53, EVI2B, CD10, and CD33. Comparison of short-term treatment with chronic resistance delineates large differences in surface proteome profile under each type of drug exposure. Finally, we develop a miniaturized version of the surface proteomics protocol and present the first surface proteomic profile of a primary malignant plasma cell sample of MM patient. Our dataset provides a unique resource to advance the biological, therapeutic, and diagnostic understanding of myeloma.

2022-05-27 | PXD022482 | Pride

Defining the cell surface proteomic landscape of multiple myeloma reveals immunotherapeutic strategies and biomarkers of drug resistance

Project description:The myeloma cell surface proteome (“surfaceome”) not only determines tumor interaction with the microenvironment but serves as an emerging arena for therapeutic development. Here, we use glycoprotein capture proteomics to first define surface markers most-enriched on myeloma when compared to B-cell malignancy models, revealing unexpected biological signatures unique to malignant plasma cells. We next integrate our proteomic dataset with existing transcriptome databases, nominating CCR10 and TXNDC11 as possible monotherapeutic targets and CD48 as a promising co-target for increasing avidity of BCMA-directed cellular therapies. We further identify potential biomarkers of resistance to proteasome inhibitors and lenalidomide including changes in CD53, EVI2B, CD10, and CD33. Comparison of short-term treatment with chronic resistance delineates large differences in surface proteome profile under each type of drug exposure. Finally, we develop a miniaturized version of the surface proteomics protocol and present the first surface proteomic profile of a primary plasma cell sample. Our dataset provides a unique resource to advance the biological, therapeutic, and diagnostic understanding of myeloma.

2021-12-10 | GSE160572 | GEO

Unbiased cell surface proteomics identifies SEMA4A as an effective immunotherapy target for myeloma

Project description:The accessibility of cell surface proteins makes them tractable for cancer immunotherapy, but identifying suitable targets remains challenging, and resistance to treatment is common. Technical difficulties precluding the use of whole cell proteomic approaches to characterize cell surface proteins include low abundance, hydrophobicity, and a lack of protease cleavage sites. Furthermore, neither whole-cell proteomic nor transcriptomic data can accurately quantify protein expression at the plasma membrane. Resistance to immunotherapies is commonly mediated by downregulation of the target protein, a particular problem when immunotherapies fail to inhibit a specific biological pathway. Here we have used plasma membrane profiling of primary human myeloma cells to identify an unprecedented number of cell surface proteins and quantify for the first time the entire cell surface proteome of a primary cancer. This approach revealed a novel therapeutic target, SEMA4A, which we potently and selectively targeted with an antibody-drug conjugate in vitro and in vivo. Reduction of SEMA4A expression resulted in marked impairment of myeloma cell growth in vitro, indicating that myeloma cells cannot downregulate SEMA4A to avoid detection. Our data therefore reveal not only a novel myeloma target but provide an exemplar of a top-down approach from the unbiased characterization of a cancer cell surface proteome to novel immunotherapeutic target.

2022-01-24 | PXD014165 | Pride

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