Browse
Submit Data
Databases
API
Help

Dataset Information

0 Views

0 Connections

0 Citations

0 Reanalyses

0 Downloads

Omics score: 0

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

ABSTRACT: 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.

INSTRUMENT(S): Q Exactive

ORGANISM(S): Homo Sapiens (human)

TISSUE(S): B Cell, Cell Suspension Culture

DISEASE(S): Multiple Myeloma

SUBMITTER: Ian Ferguson

LAB HEAD: Arun P. Wiita

PROVIDER: PXD022482 | Pride | 2022-05-27

REPOSITORIES: Pride

ACCESS DATA

Json Xml

Similar Datasets

Micro cell surface proteomics myeloma

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 MM patient plasma cell sample. Our dataset provides a unique resource to advance the biological, therapeutic, and diagnostic understanding of myeloma.

2022-05-27 | PXD022553 | Pride

Primary Myeloma Proteomics using Micro IST method

Project description:The myeloma cell surface proteome (â€œsurfaceomeâ€�) 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 MM patient plasma cell sample. Our dataset provides a unique resource to advance the biological, therapeutic, and diagnostic understanding of myeloma. Note that this is a data supplement to PXD022553.

2022-05-27 | PXD032031 | Pride

Functional multi-omics reveals genetic and pharmacologic regulation of surface CD38 in multiple myeloma

Project description:CD38 is a surface ectoenzyme expressed at high levels on myeloma plasma cells and is the target for the monoclonal antibodies (mAbs) daratumumab and isatuximab. CD38 density on tumor cells is an important determinant of mAb efficacy while CD38 is lost after mAb treatment. Several small molecules have been found to increase tumor surface CD38, with the goal of boosting mAb efficacy in a co-treatment strategy. Here we sought to extend our currently limited insight into CD38 surface expression by using a multi-omics approach. Genome-wide CRISPR-interference screens integrated with patient-centered epigenetic analysis confirmed known regulators of CD38, such as RARA, while revealing XBP1 and SPI1 as other key transcription factors governing surface CD38 levels. CD38 knockdown followed by cell surface proteomics demonstrated no significant remodeling of the myeloma “surfaceome” after genetically-induced loss of this antigen. Integrated transcriptome and surface proteome data confirmed high specificity of all-trans retinoic acid in upregulating CD38 in contrast to broader effects of azacytidine and panobinostat. Finally, unbiased phosphoproteomics identified inhibition of MAP kinase pathway signaling in tumor cells after daratumumab treatment. Our work provides a resource to design strategies to enhance efficacy of CD38-targeting immunotherapies in myeloma.

2021-07-29 | PXD027594 | Pride

TDP-43 loss of function inhibits endosomal trafficking and alters trophic signaling in neurons - Surface labelling

Project description:Nuclear clearance of TDP-43 into cytoplasmic aggregates is a key driver of neurodegeneration in amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration (FTLD), but the mechanisms are unclear. Here, we show that TDP-43 knockdown specifically reduces number and motility of RAB11-positive recycling endosomes in dendrites, while TDP-43 overexpression has the opposite effect. This is associated with delayed transferrin recycling in TDP-43 knockdown neurons and decreased 2-transferrin levels in patient CSF. Whole proteome quantification identified upregulation of the ESCRT component VPS4B upon TDP-43 knockdown in neurons. Luciferase report assays and chromatin immunoprecipitation suggest that TDP-43 represses VPS4B transcription. Preventing VPS4B upregulation or expression of its functional antagonist ALIX restores trafficking of recycling endosomes. Proteomic analysis revealed broad reduction in surface expression of key receptors upon TDP-43 knockdown including ErbB4, the neuregulin 1 receptor. TDP-43 knockdown delays surface delivery of ErbB4. ErbB4 overexpression, but not neuregulin 1 stimulation, prevents dendrite loss upon TDP-43 knockdown. Thus, impaired recycling of ErbB4 and other receptors to the cell surface may contribute to TDP-43 induced neurodegeneration by blocking trophic signaling.

2016-09-29 | PXD004744 | Pride

Cell Surface Proteome during Enterohaemorrhagic E. coli infection

Project description:Proteins on the cell surface are crucial for the interaction of a cell with its surrounding environment. Viral infection is known to remodel to the host cell surface to the benefit of the pathogen, but relatively little is known about how bacterial pathogens alter the host cell surface. Enterohaemorrhagic E. coli(EHEC) infects the apical surface of gut epithelium, and maniplates multiple aspects of host physiology. Here we used quantitative cell surface proteomics to investigate EHEC-induced changes to the host cell surface and show that the complement regulatory protein CD55 is cleaved from epithelial surfaces by the EHEC metalloprotease StcE. As a consequence of this, neutrophil attachment to the apical surface of epithelial cells is increased. This study is the first to apply quantitaive cell surface proteomics to EHEC infection and reveals a novel mechanism by which EHEC manipulates the host immune system.

2018-09-10 | PXD010361 | Pride

Ancistrocladinium A induces cell death in drug-resistant myeloma cells via targeting transcription and RNA splicing machinery and ATF4-dependent apoptotic pathway: a promising candidate as a drug for multiple myeloma

Project description:N,C-coupled naphthylisoquinoline alkaloids like the natural product ancistrocladinium A, was known for its strong antiprotozoal activity, but had never explored for its antitumor activity. We found the alkaloid to be a very efficient anti-myeloma agent in various cell lines, including proteasome inhibitor-resistant cell lines and patient's primary CD138+ myeloma cells either alone or in combination approaches with the compounds carfilzomib or panobinostat. To gain further insight, we used an MS-based approach with the biotinylated derivative of Ancistrocladinium A, leading to an enrichment of RNA splicing associated proteins. We validated alternative pre-mRNA splicing by analyzing RNA gene expression and splicing using the human Clariom D gene array after treatment of INA-6 cells with the alkaloid. Important pathways with altered RNA expression levels included RNA processing, transcription and splicing, and the ribonucleoprotein complex. Pathways with altered RNA splicing included PSMB5 target genes and, therefore, a driver of unfolded protein response (UPR) along with transcription-associated and cell cycle-associated genes. Furthermore, we confirmed the splicing-induced protein expression of activating tran-scription factor 4 (ATF4), a key regulator of UPR. Finally, histone 2A (H2A) phosphorylation and PARP-1 cleavage as an indicator of apoptosis indicator was also detected. Taken together, an-cistrocladinium A can be considered as a potent agent against PI-resistance in MM either alone or in combination with clinically approved drugs.

2023-10-24 | PXD043261 | Pride

The antigenic landscape of multiple myeloma: mass spectrometry (re)defines targets for T-cell–based immunotherapy

Project description:Direct analysis of HLA-presented antigens by mass spectrometry provides a comprehensive view on the antigenic landscape of different tissues/malignancies and enables the identification of novel, pathophysiologically relevant T-cell epitopes. Here, we present a systematic and comparative study of the HLA class I and II presented, nonmutant antigenome of multiple myeloma (MM). Quantification of HLA surface expression revealed elevated HLA molecule counts on malignant plasma cells compared with normal B cells, excluding relevant HLA downregulation in MM. Analyzing the presentation of established myeloma-associated T-cell antigens on the HLA ligandome level, we found a substantial proportion of antigens to be only infrequently presented on primary myelomas or to display suboptimal degrees of myeloma specificity. However, unsupervised analysis of our extensive HLA ligand data set delineated a panel of 58 highly specific myeloma-associated antigens (including multiple myeloma SET domain containing protein) which are characterized by frequent and exclusive presentation on myeloma samples. Functional characterization of these target antigens revealed peptide-specific, preexisting CD8+ T-cell responses exclusively in myeloma patients, which is indicative of pathophysiological relevance. Furthermore, in vitro priming experiments revealed that peptide-specific T-cell responses can be induced in response-naive myeloma patients. Together, our results serve to guide antigen selection for T-cell–based immunotherapy of MM.

2022-07-19 | PXD035324 | Pride

Microarray analysis of multiple myeloma cell line INA-6 overexpressing PRL-3 vs. Mock control cells

Project description:PRL-3 is an oncogenic phosphatase, which is expressed at a higher level in malignant plasma cells from multiple myeloma patients than in plasma cells from healthy donors and high expression is associated with a poor prognosis. We overexpressed PRL-3 in a multiple myeloma cell line and our goal was to find signaling pathways regulated by PRL-3 in myeloma cells.

2021-07-01 | E-MTAB-10436 | biostudies-arrayexpress

Candida albicans is resistant to polyglutamine aggregation and toxicity

Project description:Disruption of protein quality control can be detrimental, having toxic effects on single cell organisms, and causing neurodegenerative diseases such as Alzheimer’s, Parkinson’s and Huntington’s in humans. Here we examined the effects of polyQ aggregation in a major fungal pathogen of humans, Candida albicans, with the goal of identifying new approaches to disable this fungus. However, we discovered that expression of poly-glutamine (polyQ) stretches up to 230Q had no effect on C. albicans ability to grow and withstand proteotoxic stress. Bioinformatics analysis demonstrates that C. albicans has a similarly glutamine rich proteome to the unicellular fungus Saccharomyces cerevisiae, which exhibits polyQ toxicity with as few as 72Q. Surprisingly, global transcriptional profiles indicated no significant change upon induction of up to 230Q. Proteomic analysis highlighted two key interactors of 230Q, Sis1 and Sgt2, however, loss of either protein had no additional effect on C. albicans toxicity. Our data suggest that C. albicans has evolved powerful mechanisms to overcome aggregation prone proteins, providing a unique model for studying polyQ associated diseases.

2016-12-05 | PXD003916 | 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

OmicsDI is part of the ELIXIR infrastructure

OmicsDI is an Elixir interoperability service. Learn more ›

OmicsDI Databases

PRIDE
PeptideAtlas
MassIVE
JPOST Repository
Physiome Model Repository

EGA
EVA
ENA
LINCS
PAXDB
Cell Collective

MetaboLights
Metabolomics Workbench
MetabolomeExpress
GNPS
BioModels
FAIRDOMHub

ArrayExpress
dbGaP
ExpressionAtlas
GEO
NODE

Information

Databases
Help
API
Contact us
Code on GitHub
Terms of use
Submit Data