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Article ; Online: Feasibility of phosphoproteomics to uncover oncogenic signalling in secreted extracellular vesicles using glioblastoma-EGFRVIII cells as a model

Bijnsdorp, Irene V. / Schelfhorst, Tim / Luinenburg, Mark / Rolfs, Frank / Piersma, Sander R. / de Haas, Richard R. / Pham, Thang V. / Jimenez, Connie R.

Journal of Proteomics. 2021 Feb., v. 232 p.104076-

2021

Abstract: Cancer cells secrete extracellular vesicles (EVs) that contain molecular information, including proteins and RNA. Oncogenic signalling can be transferred via the cargo of EVs to recipient cells and may influence the behaviour of neighbouring cells or ... ...

Abstract	Cancer cells secrete extracellular vesicles (EVs) that contain molecular information, including proteins and RNA. Oncogenic signalling can be transferred via the cargo of EVs to recipient cells and may influence the behaviour of neighbouring cells or cells at a distance. This cargo may contain cancer drivers, such as EGFR, and also phosphorylated (activated) components of oncogenic signalling cascades. Till date, the cancer EV phosphoproteome has not been studied in great detail. In the present study, we used U87 and U87EGFRvIII cells as a model to explore EV oncogenic signalling components in comparison to the cellular profile. EVs were isolated using the VN96 ME-kit and subjected to LC-MS/MS based phosphoproteomics and dedicated bioinformatics. Expression of (phosphorylated)-EGFR was highly increased in EGFRvIII overexpressing cells and their secreted EVs. The increased phosphorylated proteins in both cells and EVs were associated with activated components of the EGFR-signalling cascade and included EGFR, AKT2, MAPK8, SMG1, MAP3K7, DYRK1A, RPS6KA3 and PAK4 kinases. In conclusion, EVs harbour oncogenic signalling networks including multiple activated kinases including EGFR, AKT and mTOR. Extracellular vesicles (EVs) are biomarker treasure troves and are widely studied for their biomarker content in cancer. However, little research has been done on the phosphorylated protein profile within cancer EVs. In the current study, we demonstrate that EVs that are secreted by U87-EGFRvIII mutant glioblastoma cells contain high levels of oncogenic signalling networks. These networks contain multiple activated (phosphorylated) kinases, including EGFR, MAPK, AKT and mTOR.
Keywords	RNA ; bioinformatics ; biomarkers ; glioblastoma ; models ; mutants ; phosphoproteome ; phosphotransferases (kinases) ; protein composition ; proteomics ; Glioblastoma multiforme ; Phospho-proteomics ; LC-MS/MS ; EGFR ; exosome ; Extracellular vesicles ; InKa
Language	English
Dates of publication	2021-02
Publishing place	Elsevier B.V.
Document type	Article ; Online
Note	NAL-AP-2-clean
ZDB-ID	2400835-7
ISSN	1876-7737 ; 1874-3919
ISSN (online)	1876-7737
ISSN	1874-3919
DOI	10.1016/j.jprot.2020.104076
Database	NAL-Catalogue (AGRICOLA)

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Article ; Online: Feasibility of phosphoproteomics to uncover oncogenic signalling in secreted extracellular vesicles using glioblastoma-EGFRVIII cells as a model.

Bijnsdorp, Irene V / Schelfhorst, Tim / Luinenburg, Mark / Rolfs, Frank / Piersma, Sander R / de Haas, Richard R / Pham, Thang V / Jimenez, Connie R

Journal of proteomics

2020 Volume 232, Page(s) 104076

Abstract	Cancer cells secrete extracellular vesicles (EVs) that contain molecular information, including proteins and RNA. Oncogenic signalling can be transferred via the cargo of EVs to recipient cells and may influence the behaviour of neighbouring cells or cells at a distance. This cargo may contain cancer drivers, such as EGFR, and also phosphorylated (activated) components of oncogenic signalling cascades. Till date, the cancer EV phosphoproteome has not been studied in great detail. In the present study, we used U87 and U87EGFRvIII cells as a model to explore EV oncogenic signalling components in comparison to the cellular profile. EVs were isolated using the VN96 ME-kit and subjected to LC-MS/MS based phosphoproteomics and dedicated bioinformatics. Expression of (phosphorylated)-EGFR was highly increased in EGFRvIII overexpressing cells and their secreted EVs. The increased phosphorylated proteins in both cells and EVs were associated with activated components of the EGFR-signalling cascade and included EGFR, AKT2, MAPK8, SMG1, MAP3K7, DYRK1A, RPS6KA3 and PAK4 kinases. In conclusion, EVs harbour oncogenic signalling networks including multiple activated kinases including EGFR, AKT and mTOR. SIGNIFICANCE: Extracellular vesicles (EVs) are biomarker treasure troves and are widely studied for their biomarker content in cancer. However, little research has been done on the phosphorylated protein profile within cancer EVs. In the current study, we demonstrate that EVs that are secreted by U87-EGFRvIII mutant glioblastoma cells contain high levels of oncogenic signalling networks. These networks contain multiple activated (phosphorylated) kinases, including EGFR, MAPK, AKT and mTOR.
MeSH term(s)	Chromatography, Liquid ; ErbB Receptors ; Extracellular Vesicles ; Feasibility Studies ; Glioblastoma ; Humans ; Tandem Mass Spectrometry ; p21-Activated Kinases
Chemical Substances	epidermal growth factor receptor VIII ; PAK4 protein, human (EC 2.7.1.11) ; ErbB Receptors (EC 2.7.10.1) ; p21-Activated Kinases (EC 2.7.11.1)
Language	English
Publishing date	2020-12-08
Publishing country	Netherlands
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	2400835-7
ISSN	1876-7737 ; 1874-3919
ISSN (online)	1876-7737
ISSN	1874-3919
DOI	10.1016/j.jprot.2020.104076
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Article ; Online: The influence of delay in mononuclear cell isolation on acute myeloid leukemia phosphorylation profiles

van Alphen, Carolien / Cucchi, David G.J. / Cloos, Jacqueline / Schelfhorst, Tim / Henneman, Alexander A. / Piersma, Sander R. / Pham, Thang V. / Knol, Jaco C. / Jimenez, Connie R. / Janssen, Jeroen J.W.M.

Journal of Proteomics. 2021 Apr., v. 238 p.104134-

2021

Abstract: Mass-spectrometry (MS) based phosphoproteomics is increasingly used to explore aberrant cellular signaling and kinase driver activity, aiming to improve kinase inhibitor (KI) treatment selection in malignancies. Phosphorylation is a dynamic, highly ... ...

Abstract	Mass-spectrometry (MS) based phosphoproteomics is increasingly used to explore aberrant cellular signaling and kinase driver activity, aiming to improve kinase inhibitor (KI) treatment selection in malignancies. Phosphorylation is a dynamic, highly regulated post-translational modification that may be affected by variation in pre-analytical sample handling, hampering the translational value of phosphoproteomics-based analyses. Here, we investigate the effect of delay in mononuclear cell isolation on acute myeloid leukemia (AML) phosphorylation profiles. We performed MS on immuno-precipitated phosphotyrosine (pY)-containing peptides isolated from AML samples after seven pre-defined delays before sample processing (direct processing, thirty minutes, one hour, two hours, three hours, four hours and 24 h delay). Up to four hours, pY phosphoproteomics profiles show limited variation. However, in samples processed with a delay of 24 h, we observed significant change in these phosphorylation profiles, with differential phosphorylation of 22 pY phosphopeptides (p < 0.01). This includes increased phosphorylation of pY phosphopeptides of JNK and p38 kinases indicative of stress response activation. Based on these results, we conclude that processing of AML samples should be standardized at all times and should occur within four hours after sample collection. Our study provides a practical time-frame in which fresh peripheral blood samples from acute myeloid patients should be processed for phosphoproteomics, in order to warrant correct interpretation of in vivo biology. We show that up to four hours of delayed processing after sample collection, pY phosphoproteomic profiles remain stable. Extended delays are associated with perturbation of phosphorylation profiles. After a delay of 24 h, JNK activation loop phosphorylation is markedly increased and may serve as a biomarker for delayed processing. These findings are relevant for biomedical acute myeloid leukemia research, as phosphoproteomic techniques are of particular interest to investigate aberrant kinase signaling in relation to disease emergence and kinase inhibitor response. With these data, we aim to contribute to reproducible research with meaningful outcomes.
Keywords	biomarkers ; blood ; mass spectrometry ; myeloid leukemia ; phosphopeptides ; phosphorylation ; phosphotransferases (kinases) ; post-translational modification ; proteomics ; stress response ; Acute myeloid leukemia ; AML ; Phosphoproteomics ; Phosphotyrosine ; Ischemia ; Oxidative stress ; Preanalytical variables ; Tyrosine kinase ; INKA
Language	English
Dates of publication	2021-04
Publishing place	Elsevier B.V.
Document type	Article ; Online
Note	NAL-AP-2-clean ; Use and reproduction
ZDB-ID	2400835-7
ISSN	1876-7737 ; 1874-3919
ISSN (online)	1876-7737
ISSN	1874-3919
DOI	10.1016/j.jprot.2021.104134
Database	NAL-Catalogue (AGRICOLA)

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Article ; Online: Fsp1-Mediated Lineage Tracing Fails to Detect the Majority of Disseminating Cells Undergoing EMT.

Bornes, Laura / van Scheppingen, Roan Hugo / Beerling, Evelyne / Schelfhorst, Tim / Ellenbroek, Saskia Inge Johanna / Seinstra, Danielle / van Rheenen, Jacco

Cell reports

2019 Volume 29, Issue 9, Page(s) 2565–2569.e3

Abstract: Epithelial-to-mesenchymal transition (EMT) has long been thought to be crucial for metastasis. Recently a study challenged this idea by demonstrating that metastases were seeded by tumor cells that were not marked by an EMT lineage-tracing reporter on ... ...

Abstract	Epithelial-to-mesenchymal transition (EMT) has long been thought to be crucial for metastasis. Recently a study challenged this idea by demonstrating that metastases were seeded by tumor cells that were not marked by an EMT lineage-tracing reporter on the basis of the expression of the mesenchymal marker fsp1. However, the results of this study and their interpretation are under debate. Here, we combine the lineage-tracing reporter with our real-time EMT-state reporter and show that the fsp1-based EMT lineage-tracing reporter does not mark all disseminating mesenchymal cells with metastatic potential. Our findings demonstrate that fsp1-mediated lineage tracing does not allow any conclusions about the requirement of EMT for metastasis. Instead our data are fully consistent with previous reports that EMT is not a binary phenomenon but rather a spectrum of cellular states.
MeSH term(s)	Epithelial Cells/metabolism ; Epithelial-Mesenchymal Transition/immunology ; Humans
Language	English
Publishing date	2019-11-26
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	2649101-1
ISSN	2211-1247 ; 2211-1247
ISSN (online)	2211-1247
ISSN	2211-1247
DOI	10.1016/j.celrep.2019.10.107
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Article: Sex-Related Differences in Protein Expression in Sarcomere Mutation-Positive Hypertrophic Cardiomyopathy.

Schuldt, Maike / Dorsch, Larissa M / Knol, Jaco C / Pham, Thang V / Schelfhorst, Tim / Piersma, Sander R / Dos Remedios, Cris / Michels, Michelle / Jimenez, Connie R / Kuster, Diederik W D / van der Velden, Jolanda

Frontiers in cardiovascular medicine

2021 Volume 8, Page(s) 612215

Abstract: Background: ...

Abstract	Background:
Language	English
Publishing date	2021-03-01
Publishing country	Switzerland
Document type	Journal Article
ZDB-ID	2781496-8
ISSN	2297-055X
ISSN	2297-055X
DOI	10.3389/fcvm.2021.612215
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Article ; Online: The influence of delay in mononuclear cell isolation on acute myeloid leukemia phosphorylation profiles.

van Alphen, Carolien / Cucchi, David G J / Cloos, Jacqueline / Schelfhorst, Tim / Henneman, Alexander A / Piersma, Sander R / Pham, Thang V / Knol, Jaco C / Jimenez, Connie R / Janssen, Jeroen J W M

Journal of proteomics

2021 Volume 238, Page(s) 104134

Abstract	Mass-spectrometry (MS) based phosphoproteomics is increasingly used to explore aberrant cellular signaling and kinase driver activity, aiming to improve kinase inhibitor (KI) treatment selection in malignancies. Phosphorylation is a dynamic, highly regulated post-translational modification that may be affected by variation in pre-analytical sample handling, hampering the translational value of phosphoproteomics-based analyses. Here, we investigate the effect of delay in mononuclear cell isolation on acute myeloid leukemia (AML) phosphorylation profiles. We performed MS on immuno-precipitated phosphotyrosine (pY)-containing peptides isolated from AML samples after seven pre-defined delays before sample processing (direct processing, thirty minutes, one hour, two hours, three hours, four hours and 24 h delay). Up to four hours, pY phosphoproteomics profiles show limited variation. However, in samples processed with a delay of 24 h, we observed significant change in these phosphorylation profiles, with differential phosphorylation of 22 pY phosphopeptides (p < 0.01). This includes increased phosphorylation of pY phosphopeptides of JNK and p38 kinases indicative of stress response activation. Based on these results, we conclude that processing of AML samples should be standardized at all times and should occur within four hours after sample collection. SIGNIFICANCE: Our study provides a practical time-frame in which fresh peripheral blood samples from acute myeloid patients should be processed for phosphoproteomics, in order to warrant correct interpretation of in vivo biology. We show that up to four hours of delayed processing after sample collection, pY phosphoproteomic profiles remain stable. Extended delays are associated with perturbation of phosphorylation profiles. After a delay of 24 h, JNK activation loop phosphorylation is markedly increased and may serve as a biomarker for delayed processing. These findings are relevant for biomedical acute myeloid leukemia research, as phosphoproteomic techniques are of particular interest to investigate aberrant kinase signaling in relation to disease emergence and kinase inhibitor response. With these data, we aim to contribute to reproducible research with meaningful outcomes.
MeSH term(s)	Cell Separation ; Humans ; Leukemia, Myeloid, Acute ; Phosphorylation ; Phosphotyrosine/metabolism ; Proteomics
Chemical Substances	Phosphotyrosine (21820-51-9)
Language	English
Publishing date	2021-02-06
Publishing country	Netherlands
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	2400835-7
ISSN	1876-7737 ; 1874-3919
ISSN (online)	1876-7737
ISSN	1874-3919
DOI	10.1016/j.jprot.2021.104134
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Article ; Online: Neutrophil degranulation interconnects over-represented biological processes in atrial fibrillation.

Kawasaki, Makiri / Meulendijks, Eva R / van den Berg, Nicoline W E / Nariswari, Fransisca A / Neefs, Jolien / Wesselink, Robin / Baalman, Sarah W E / Jongejan, Aldo / Schelfhorst, Tim / Piersma, Sander R / Pham, Thang V / van Boven, Wim J P / Driessen, Antoine H G / Jimenez, Connie R / de Groot, Joris R

Scientific reports

2021 Volume 11, Issue 1, Page(s) 2972

Abstract: Despite our expanding knowledge about the mechanism underlying atrial fibrillation (AF), the interplay between the biological events underlying AF remains incompletely understood. This study aimed to identify the functionally enriched gene-sets in AF and ...

Abstract	Despite our expanding knowledge about the mechanism underlying atrial fibrillation (AF), the interplay between the biological events underlying AF remains incompletely understood. This study aimed to identify the functionally enriched gene-sets in AF and capture their interconnection via pivotal factors, that may drive or be driven by AF. Global abundance of the proteins in the left atrium of AF patients compared to control patients (n = 3/group), and the functionally enriched biological processes in AF were determined by mass-spectrometry and gene set enrichment analysis, respectively. The data were validated in an independent cohort (n = 19-20/group). In AF, the gene-sets of innate immune system, metabolic process, cellular component disassembly and ion homeostasis were up-regulated, while the gene-set of ciliogenesis was down-regulated. The innate immune system was over-represented by neutrophil degranulation, the components of which were extensively shared by other gene-sets altered in AF. In the independent cohort, an activated form of neutrophils was more present in the left atrium of AF patients with the increased gene expression of neutrophil granules. MYH10, required for ciliogenesis, was decreased in the atrial fibroblasts of AF patients. We report the increased neutrophil degranulation appears to play a pivotal role, and affects multiple biological processes altered in AF.
MeSH term(s)	Atrial Fibrillation/immunology ; Atrial Fibrillation/pathology ; Atrial Fibrillation/surgery ; Case-Control Studies ; Catheter Ablation ; Cell Degranulation/immunology ; Fibroblasts/metabolism ; Heart Atria/immunology ; Heart Atria/pathology ; Humans ; Male ; Myosin Heavy Chains/metabolism ; Neutrophil Activation ; Neutrophils/immunology ; Neutrophils/metabolism ; Nonmuscle Myosin Type IIB/metabolism ; Proteomics
Chemical Substances	Nonmuscle Myosin Type IIB (EC 3.6.1.-) ; nonmuscle myosin type IIB heavy chain (EC 3.6.1.-) ; Myosin Heavy Chains (EC 3.6.4.1)
Language	English
Publishing date	2021-02-03
Publishing country	England
Document type	Journal Article
ZDB-ID	2615211-3
ISSN	2045-2322 ; 2045-2322
ISSN (online)	2045-2322
ISSN	2045-2322
DOI	10.1038/s41598-021-82533-5
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Article ; Online: Taxanes trigger cancer cell killing in vivo by inducing non-canonical T cell cytotoxicity.

Vennin, Claire / Cattaneo, Chiara M / Bosch, Leontien / Vegna, Serena / Ma, Xuhui / Damstra, Hugo G J / Martinovic, Moreno / Tsouri, Efi / Ilic, Mila / Azarang, Leyla / van Weering, Jan R T / Pulver, Emilia / Zeeman, Amber L / Schelfhorst, Tim / Lohuis, Jeroen O / Rios, Anne C / Dekkers, Johanna F / Akkari, Leila / Menezes, Renee /

Medema, Rene / Baglio, Serena R / Akhmanova, Anna / Linn, Sabine C / Lemeer, Simone / Pegtel, Dirk M / Voest, Emile E / van Rheenen, Jacco

Cancer cell

2023 Volume 41, Issue 6, Page(s) 1170–1185.e12

Abstract: Although treatment with taxanes does not always lead to clinical benefit, all patients are at risk of their detrimental side effects such as peripheral neuropathy. Understanding the in vivo mode of action of taxanes can help design improved treatment ... ...

Abstract	Although treatment with taxanes does not always lead to clinical benefit, all patients are at risk of their detrimental side effects such as peripheral neuropathy. Understanding the in vivo mode of action of taxanes can help design improved treatment regimens. Here, we demonstrate that in vivo, taxanes directly trigger T cells to selectively kill cancer cells in a non-canonical, T cell receptor-independent manner. Mechanistically, taxanes induce T cells to release cytotoxic extracellular vesicles, which lead to apoptosis specifically in tumor cells while leaving healthy epithelial cells intact. We exploit these findings to develop an effective therapeutic approach, based on transfer of T cells pre-treated with taxanes ex vivo, thereby avoiding toxicity of systemic treatment. Our study reveals a different in vivo mode of action of one of the most commonly used chemotherapies, and opens avenues to harness T cell-dependent anti-tumor effects of taxanes while avoiding systemic toxicity.
MeSH term(s)	Humans ; T-Lymphocytes ; Taxoids/pharmacology ; Apoptosis ; Epithelial Cells ; Extracellular Vesicles ; Neoplasms/drug therapy
Chemical Substances	Taxoids
Language	English
Publishing date	2023-06-11
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	2078448-X
ISSN	1878-3686 ; 1535-6108
ISSN (online)	1878-3686
ISSN	1535-6108
DOI	10.1016/j.ccell.2023.05.009
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Zs.A 5650: Show issues			Location: Je nach Verfügbarkeit (siehe Angabe bei Bestand) bis Jg. 1994: Bestellungen von Artikeln über das Online-Bestellformular Jg. 1995 - 2021: Lesesall (2.OG) ab Jg. 2022: Lesesaal (EG)
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Article ; Online: Proteomic Analysis of miR-195 and miR-497 Replacement Reveals Potential Candidates that Increase Sensitivity to Oxaliplatin in MSI/P53wt Colorectal Cancer Cells.

Poel, Dennis / Boyd, Lenka N C / Beekhof, Robin / Schelfhorst, Tim / Pham, Thang V / Piersma, Sander R / Knol, Jaco C / Jimenez, Connie R / Verheul, Henk M W / Buffart, Tineke E

Cells

2019 Volume 8, Issue 9

Abstract: Most patients with advanced colorectal cancer (CRC) eventually develop resistance to systemic combination therapy. miR-195-5p and miR-497-5p are downregulated in CRC tissues and associated with drug resistance. Sensitization to 5-FU, oxaliplatin, and ... ...

Abstract	Most patients with advanced colorectal cancer (CRC) eventually develop resistance to systemic combination therapy. miR-195-5p and miR-497-5p are downregulated in CRC tissues and associated with drug resistance. Sensitization to 5-FU, oxaliplatin, and irinotecan by transfection with miR-195-5p and miR-497-5p mimics was studied using cell viability and clonogenic assays in cell lines HCT116, RKO, DLD-1, and SW480. In addition, proteomic analysis of transfected cells was implemented to identify potential targets. Significantly altered proteins were subjected to STRING (protein-protein interaction networks) database analysis to study the potential mechanisms of drug resistance. Cell viability analysis of transfected cells revealed increased sensitivity to oxaliplatin in microsatellite instable (MSI)/P53 wild-type HCT116 and RKO cells. HCT116 transfected cells formed significantly fewer colonies when treated with oxaliplatin. In sensitized cells, proteomic analysis showed 158 and 202 proteins with significantly altered expression after transfection with miR-195-5p and miR-497-5p mimics respectively, of which CHUK and LUZP1 proved to be coinciding downregulated proteins. Resistance mechanisms of these proteins may be associated with nuclear factor kappa-B signaling and G1 cell-cycle arrest. In conclusion, miR-195-5p and miR-497-5p replacement enhanced sensitivity to oxaliplatin in treatment naïve MSI/P53 wild-type CRC cells. Proteomic analysis revealed potential miRNA targets associated with the cell-cycle which possibly bare a relation with chemotherapy sensitivity.
MeSH term(s)	Antineoplastic Agents/pharmacology ; Cell Proliferation/drug effects ; Cell Survival/drug effects ; Colorectal Neoplasms/drug therapy ; Colorectal Neoplasms/metabolism ; Colorectal Neoplasms/pathology ; HCT116 Cells ; Humans ; MicroRNAs/analysis ; MicroRNAs/genetics ; Microsatellite Instability/drug effects ; Oxaliplatin/pharmacology ; Proteomics ; RNA, Messenger/analysis ; RNA, Messenger/genetics ; Tumor Cells, Cultured ; Tumor Suppressor Protein p53/antagonists & inhibitors ; Tumor Suppressor Protein p53/metabolism
Chemical Substances	Antineoplastic Agents ; MIRN195 microRNA, human ; MIRN497 microRNA, human ; MicroRNAs ; RNA, Messenger ; Tumor Suppressor Protein p53 ; Oxaliplatin (04ZR38536J)
Language	English
Publishing date	2019-09-19
Publishing country	Switzerland
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	2661518-6
ISSN	2073-4409 ; 2073-4409
ISSN (online)	2073-4409
ISSN	2073-4409
DOI	10.3390/cells8091111
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Article ; Online: Proteomic and Functional Studies Reveal Detyrosinated Tubulin as Treatment Target in Sarcomere Mutation-Induced Hypertrophic Cardiomyopathy.

Schuldt, Maike / Pei, Jiayi / Harakalova, Magdalena / Dorsch, Larissa M / Schlossarek, Saskia / Mokry, Michal / Knol, Jaco C / Pham, Thang V / Schelfhorst, Tim / Piersma, Sander R / Dos Remedios, Cris / Dalinghaus, Michiel / Michels, Michelle / Asselbergs, Folkert W / Moutin, Marie-Jo / Carrier, Lucie / Jimenez, Connie R / van der Velden, Jolanda / Kuster, Diederik W D

Circulation. Heart failure

2021 Volume 14, Issue 1, Page(s) e007022

Abstract: Background: Hypertrophic cardiomyopathy (HCM) is the most common genetic heart disease. While ≈50% of patients with HCM carry a sarcomere gene mutation (sarcomere mutation-positive, HCM: Methods: A proteomics screen was performed in cardiac tissue ... ...

Abstract	Background: Hypertrophic cardiomyopathy (HCM) is the most common genetic heart disease. While ≈50% of patients with HCM carry a sarcomere gene mutation (sarcomere mutation-positive, HCM Methods: A proteomics screen was performed in cardiac tissue from 39 HCM Results: In all HCM patient samples, we found lower levels of metabolic pathway proteins and higher levels of extracellular matrix proteins. Levels of total and detyrosinated α-tubulin were markedly higher in HCM Conclusions: Our findings indicate that microtubules and especially its detyrosination contribute to the pathomechanism of patients with HCM
MeSH term(s)	Adult ; Aged ; Animals ; Cardiac Myosins/genetics ; Cardiomyopathy, Hypertrophic/genetics ; Cardiomyopathy, Hypertrophic/metabolism ; Cardiomyopathy, Hypertrophic/physiopathology ; Carrier Proteins/genetics ; Case-Control Studies ; Disease Models, Animal ; Female ; Haploinsufficiency ; Humans ; Male ; Middle Aged ; Myosin Heavy Chains/genetics ; Proteomics ; Sarcomeres/genetics ; Troponin I/genetics ; Troponin T/genetics ; Tubulin/metabolism ; Tyrosine/metabolism ; Ventricular Outflow Obstruction/genetics ; Ventricular Outflow Obstruction/metabolism ; Ventricular Outflow Obstruction/physiopathology ; Ventricular Septum/metabolism
Chemical Substances	Carrier Proteins ; MYH7 protein, human ; TNNI3 protein, human ; TNNT2 protein, human ; Troponin I ; Troponin T ; Tubulin ; myosin-binding protein C ; Tyrosine (42HK56048U) ; Cardiac Myosins (EC 3.6.1.-) ; Myosin Heavy Chains (EC 3.6.4.1)
Language	English
Publishing date	2021-01-12
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	2429459-7
ISSN	1941-3297 ; 1941-3289
ISSN (online)	1941-3297
ISSN	1941-3289
DOI	10.1161/CIRCHEARTFAILURE.120.007022
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