Deep Membrane Proteome Profiling Reveals Overexpression of Prostate-Specific Membrane Antigen (PSMA) in High-Risk Human Paraganglioma and Pheochromocytoma, Suggesting New Theranostic Opportunity

Pheochromocytomas and paragangliomas (PPGLs) are rare neuroendocrine tumors arising from chromaffin cells of adrenal medulla or sympathetic or parasympathetic paraganglia, respectively. To identify new therapeutic targets, we performed a detailed membrane-focused proteomic analysis of five human par...

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Autores principales:	Ondrej Vit, Mayank Patel, Zdenek Musil, Igor Hartmann, Zdenek Frysak, Markku Miettinen, Karel Pacak, Jiri Petrak
Formato:	article
Lenguaje:	EN
Publicado:	MDPI AG 2021
Materias:	neuroendocrine cancer pheochromocytoma paraganglioma membrane proteomics integral membrane proteins Pitchfork Organic chemistry QD241-441
Acceso en línea:	https://doaj.org/article/14efd9a646c84c37b9eeece5bb72d5b5
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spelling	oai:doaj.org-article:14efd9a646c84c37b9eeece5bb72d5b52021-11-11T18:32:57ZDeep Membrane Proteome Profiling Reveals Overexpression of Prostate-Specific Membrane Antigen (PSMA) in High-Risk Human Paraganglioma and Pheochromocytoma, Suggesting New Theranostic Opportunity10.3390/molecules262165671420-3049https://doaj.org/article/14efd9a646c84c37b9eeece5bb72d5b52021-10-01T00:00:00Zhttps://www.mdpi.com/1420-3049/26/21/6567https://doaj.org/toc/1420-3049Pheochromocytomas and paragangliomas (PPGLs) are rare neuroendocrine tumors arising from chromaffin cells of adrenal medulla or sympathetic or parasympathetic paraganglia, respectively. To identify new therapeutic targets, we performed a detailed membrane-focused proteomic analysis of five human paraganglioma (PGL) samples. Using the Pitchfork strategy, which combines specific enrichments of glycopeptides, hydrophobic transmembrane segments, and non-glycosylated extra-membrane peptides, we identified over 1800 integral membrane proteins (IMPs). We found 45 “tumor enriched” proteins, i.e., proteins identified in all five PGLs but not found in control chromaffin tissue. Among them, 18 IMPs were predicted to be localized on the cell surface, a preferred drug targeting site, including prostate-specific membrane antigen (PSMA), a well-established target for nuclear imaging and therapy of advanced prostate cancer. Using specific antibodies, we verified PSMA expression in 22 well-characterized human PPGL samples. Compared to control chromaffin tissue, PSMA was markedly overexpressed in high-risk PPGLs belonging to the established Cluster 1, which is characterized by worse clinical outcomes, pseudohypoxia, multiplicity, recurrence, and metastasis, specifically including <i>SDHB, VHL,</i> and <i>EPAS1</i> mutations. Using immunohistochemistry, we localized PSMA expression to tumor vasculature. Our study provides the first direct evidence of PSMA overexpression in PPGLs which could translate to therapeutic and diagnostic applications of anti-PSMA radio-conjugates in high-risk PPGLs.Ondrej VitMayank PatelZdenek MusilIgor HartmannZdenek FrysakMarkku MiettinenKarel PacakJiri PetrakMDPI AGarticleneuroendocrine cancerpheochromocytomaparagangliomamembrane proteomicsintegral membrane proteinsPitchforkOrganic chemistryQD241-441ENMolecules, Vol 26, Iss 6567, p 6567 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	neuroendocrine cancer pheochromocytoma paraganglioma membrane proteomics integral membrane proteins Pitchfork Organic chemistry QD241-441
spellingShingle	neuroendocrine cancer pheochromocytoma paraganglioma membrane proteomics integral membrane proteins Pitchfork Organic chemistry QD241-441 Ondrej Vit Mayank Patel Zdenek Musil Igor Hartmann Zdenek Frysak Markku Miettinen Karel Pacak Jiri Petrak Deep Membrane Proteome Profiling Reveals Overexpression of Prostate-Specific Membrane Antigen (PSMA) in High-Risk Human Paraganglioma and Pheochromocytoma, Suggesting New Theranostic Opportunity
description	Pheochromocytomas and paragangliomas (PPGLs) are rare neuroendocrine tumors arising from chromaffin cells of adrenal medulla or sympathetic or parasympathetic paraganglia, respectively. To identify new therapeutic targets, we performed a detailed membrane-focused proteomic analysis of five human paraganglioma (PGL) samples. Using the Pitchfork strategy, which combines specific enrichments of glycopeptides, hydrophobic transmembrane segments, and non-glycosylated extra-membrane peptides, we identified over 1800 integral membrane proteins (IMPs). We found 45 “tumor enriched” proteins, i.e., proteins identified in all five PGLs but not found in control chromaffin tissue. Among them, 18 IMPs were predicted to be localized on the cell surface, a preferred drug targeting site, including prostate-specific membrane antigen (PSMA), a well-established target for nuclear imaging and therapy of advanced prostate cancer. Using specific antibodies, we verified PSMA expression in 22 well-characterized human PPGL samples. Compared to control chromaffin tissue, PSMA was markedly overexpressed in high-risk PPGLs belonging to the established Cluster 1, which is characterized by worse clinical outcomes, pseudohypoxia, multiplicity, recurrence, and metastasis, specifically including <i>SDHB, VHL,</i> and <i>EPAS1</i> mutations. Using immunohistochemistry, we localized PSMA expression to tumor vasculature. Our study provides the first direct evidence of PSMA overexpression in PPGLs which could translate to therapeutic and diagnostic applications of anti-PSMA radio-conjugates in high-risk PPGLs.
format	article
author	Ondrej Vit Mayank Patel Zdenek Musil Igor Hartmann Zdenek Frysak Markku Miettinen Karel Pacak Jiri Petrak
author_facet	Ondrej Vit Mayank Patel Zdenek Musil Igor Hartmann Zdenek Frysak Markku Miettinen Karel Pacak Jiri Petrak
author_sort	Ondrej Vit
title	Deep Membrane Proteome Profiling Reveals Overexpression of Prostate-Specific Membrane Antigen (PSMA) in High-Risk Human Paraganglioma and Pheochromocytoma, Suggesting New Theranostic Opportunity
title_short	Deep Membrane Proteome Profiling Reveals Overexpression of Prostate-Specific Membrane Antigen (PSMA) in High-Risk Human Paraganglioma and Pheochromocytoma, Suggesting New Theranostic Opportunity
title_full	Deep Membrane Proteome Profiling Reveals Overexpression of Prostate-Specific Membrane Antigen (PSMA) in High-Risk Human Paraganglioma and Pheochromocytoma, Suggesting New Theranostic Opportunity
title_fullStr	Deep Membrane Proteome Profiling Reveals Overexpression of Prostate-Specific Membrane Antigen (PSMA) in High-Risk Human Paraganglioma and Pheochromocytoma, Suggesting New Theranostic Opportunity
title_full_unstemmed	Deep Membrane Proteome Profiling Reveals Overexpression of Prostate-Specific Membrane Antigen (PSMA) in High-Risk Human Paraganglioma and Pheochromocytoma, Suggesting New Theranostic Opportunity
title_sort	deep membrane proteome profiling reveals overexpression of prostate-specific membrane antigen (psma) in high-risk human paraganglioma and pheochromocytoma, suggesting new theranostic opportunity
publisher	MDPI AG
publishDate	2021
url	https://doaj.org/article/14efd9a646c84c37b9eeece5bb72d5b5
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Deep Membrane Proteome Profiling Reveals Overexpression of Prostate-Specific Membrane Antigen (PSMA) in High-Risk Human Paraganglioma and Pheochromocytoma, Suggesting New Theranostic Opportunity

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