Circulating biomarkers in familial cerebral cavernous malformationResearch in context
Summary: Background: Cerebral Cavernous Malformation (CCM) is a rare cerebrovascular disease, characterized by the presence of multiple vascular malformations that may result in intracerebral hemorrhages (ICHs), seizure(s), or focal neurological deficits (FND). Familial CCM (fCCM) is due to loss of...
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| Format: | Article |
| Language: | English |
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Elsevier
2024-01-01
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| Series: | EBioMedicine |
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| Online Access: | http://www.sciencedirect.com/science/article/pii/S2352396423004802 |
| _version_ | 1797386771413073920 |
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| author | Francesca Lazzaroni Jennifer M.T.A. Meessen Ying Sun Silvia Lanfranconi Elisa Scola Quintino Giorgio D'Alessandris Laura Tassi Maria Rita Carriero Marco Castori Silvia Marino Adriana Blanda Enrico B. Nicolis Deborah Novelli Roberta Calabrese Nicolò M. Agnelli Barbara Bottazzi Roberto Leone Selene Mazzola Silvia Besana Carlotta Catozzi Luigi Nezi Maria G. Lampugnani Matteo Malinverno Nastasja Grdseloff Claudia J. Rödel Behnam Rezai Jahromi Niccolò Bolli Francesco Passamonti Peetra U. Magnusson Salim Abdelilah-Seyfried Elisabetta Dejana Roberto Latini |
| author_facet | Francesca Lazzaroni Jennifer M.T.A. Meessen Ying Sun Silvia Lanfranconi Elisa Scola Quintino Giorgio D'Alessandris Laura Tassi Maria Rita Carriero Marco Castori Silvia Marino Adriana Blanda Enrico B. Nicolis Deborah Novelli Roberta Calabrese Nicolò M. Agnelli Barbara Bottazzi Roberto Leone Selene Mazzola Silvia Besana Carlotta Catozzi Luigi Nezi Maria G. Lampugnani Matteo Malinverno Nastasja Grdseloff Claudia J. Rödel Behnam Rezai Jahromi Niccolò Bolli Francesco Passamonti Peetra U. Magnusson Salim Abdelilah-Seyfried Elisabetta Dejana Roberto Latini |
| author_sort | Francesca Lazzaroni |
| collection | DOAJ |
| description | Summary: Background: Cerebral Cavernous Malformation (CCM) is a rare cerebrovascular disease, characterized by the presence of multiple vascular malformations that may result in intracerebral hemorrhages (ICHs), seizure(s), or focal neurological deficits (FND). Familial CCM (fCCM) is due to loss of function mutations in one of the three independent genes KRIT1 (CCM1), Malcavernin (CCM2), or Programmed Cell death 10 (PDCD10/CCM3). The aim of this study was to identify plasma protein biomarkers of fCCM to assess the severity of the disease and predict its progression. Methods: Here, we have investigated plasma samples derived from n = 71 symptomatic fCCM patients (40 female/31 male) and n = 17 healthy donors (HD) (9 female/8 male) of the Phase 1/2 Treat_CCM trial, using multiplexed protein profiling approaches. Findings: Biomarkers as sCD14 (p = 0.00409), LBP (p = 0.02911), CXCL4 (p = 0.038), ICAM-1 (p = 0.02013), ANG2 (p = 0.026), CCL5 (p = 0.00403), THBS1 (p = 0.0043), CRP (p = 0.0092), and HDL (p = 0.027), were significantly different in fCCM compared to HDs. Of note, sENG (p = 0.011), THBS1 (p = 0.011) and CXCL4 (p = 0.011), were correlated to CCM genotype. sROBO4 (p = 0.014), TM (p = 0.026) and CRP (p = 0.040) were able to predict incident adverse clinical events, such as ICH, FND or seizure. GDF-15, FLT3L, CXCL9, FGF-21 and CDCP1, were identified as predictors of the formation of new MRI-detectable lesions over 2-year follow-up. Furthermore, the functional relevance of ang2, thbs1, robo4 and cdcp1 markers was validated by zebrafish pre-clinical model of fCCM. Interpretation: Overall, our study identifies a set of biochemical parameters to predict CCM progression, suggesting biological interpretations and potential therapeutic approaches to CCM disease. Funding: Italian Medicines Agency, Associazione Italiana per la Ricerca sul Cancro (AIRC), ERC, Leducq Transatlantic Network of Excellence, Swedish Research Council. |
| first_indexed | 2024-03-08T22:14:10Z |
| format | Article |
| id | doaj.art-5d07c7a73f1a46f0b5225cf9e0e0aa36 |
| institution | Directory Open Access Journal |
| issn | 2352-3964 |
| language | English |
| last_indexed | 2024-03-08T22:14:10Z |
| publishDate | 2024-01-01 |
| publisher | Elsevier |
| record_format | Article |
| series | EBioMedicine |
| spelling | doaj.art-5d07c7a73f1a46f0b5225cf9e0e0aa362023-12-19T04:17:08ZengElsevierEBioMedicine2352-39642024-01-0199104914Circulating biomarkers in familial cerebral cavernous malformationResearch in contextFrancesca Lazzaroni0Jennifer M.T.A. Meessen1Ying Sun2Silvia Lanfranconi3Elisa Scola4Quintino Giorgio D'Alessandris5Laura Tassi6Maria Rita Carriero7Marco Castori8Silvia Marino9Adriana Blanda10Enrico B. Nicolis11Deborah Novelli12Roberta Calabrese13Nicolò M. Agnelli14Barbara Bottazzi15Roberto Leone16Selene Mazzola17Silvia Besana18Carlotta Catozzi19Luigi Nezi20Maria G. Lampugnani21Matteo Malinverno22Nastasja Grdseloff23Claudia J. Rödel24Behnam Rezai Jahromi25Niccolò Bolli26Francesco Passamonti27Peetra U. Magnusson28Salim Abdelilah-Seyfried29Elisabetta Dejana30Roberto Latini31Vascular Biology Unit, IFOM ETS-The AIRC Institute of Molecular Oncology, Milan, Italy; Hematology Department, Fondazione IRCCS Cà Granda Ospedale Maggiore Policlinico, Milan, Italy; Corresponding author. Hematology Department, Fondazione IRCCS Cà Granda Ospedale Maggiore Policlinico, Via Francesco Sforza 35, 20122, Milan, Italy.Department of Acute Brain and Cardiovascular Injury, Institute for Pharmacological Research Mario Negri IRCCS, Milan, ItalyDepartment of Immunology, Genetics and Pathology, Uppsala University, Uppsala, SwedenDepartment of Neurology, Fondazione IRCCS Cà Granda Ospedale Maggiore Policlinico, Milan, ItalyDepartment of Neurology, Fondazione IRCCS Cà Granda Ospedale Maggiore Policlinico, Milan, ItalyDepartment of Neurosurgery, Fondazione Policlinico Universitario Agostino Gemelli IRCCS, Rome, Italy; Department of Neuroscience, Università Cattolica del Sacro Cuore, Roma, ItalyClaudio Munari Epilepsy Surgery Centre, ASST Niguarda Hospital, Milan, ItalyCerebrovascular Disease Unit, Fondazione IRCCS Istituto Neurologico Carlo Besta, Milan, ItalyDivision of Medical Genetics, Fondazione IRCCS Casa Sollievo della Sofferenza, San Giovanni Rotondo, ItalyIRCCS Centro Neurolesi “Bonino Pulejo”, Messina, ItalyDepartment of Acute Brain and Cardiovascular Injury, Institute for Pharmacological Research Mario Negri IRCCS, Milan, ItalyDepartment of Acute Brain and Cardiovascular Injury, Institute for Pharmacological Research Mario Negri IRCCS, Milan, ItalyDepartment of Acute Brain and Cardiovascular Injury, Institute for Pharmacological Research Mario Negri IRCCS, Milan, ItalyDepartment of Acute Brain and Cardiovascular Injury, Institute for Pharmacological Research Mario Negri IRCCS, Milan, ItalyDepartment of Acute Brain and Cardiovascular Injury, Institute for Pharmacological Research Mario Negri IRCCS, Milan, ItalyIRCCS Humanitas Research Hospital, Rozzano, ItalyIRCCS Humanitas Research Hospital, Rozzano, ItalyLaboratory Medicine, Desio Hospital, Università Milano Bicocca, Milan, ItalyLaboratory Medicine, Desio Hospital, Università Milano Bicocca, Milan, ItalyDepartment of Experimental Oncology, Istituto Europeo di Oncologia IRCCS, Milano, ItalyDepartment of Experimental Oncology, Istituto Europeo di Oncologia IRCCS, Milano, ItalyVascular Biology Unit, IFOM ETS-The AIRC Institute of Molecular Oncology, Milan, Italy; Department of Acute Brain and Cardiovascular Injury, Institute for Pharmacological Research Mario Negri IRCCS, Milan, ItalyVascular Biology Unit, IFOM ETS-The AIRC Institute of Molecular Oncology, Milan, ItalyDepartment of Zoophysiology, Institute of Biochemistry and Biology, University of Potsdam, GermanyDepartment of Zoophysiology, Institute of Biochemistry and Biology, University of Potsdam, GermanyDepartment of Neurosurgery, Helsinki University Hospital, Helsinki, FinlandHematology Department, Fondazione IRCCS Cà Granda Ospedale Maggiore Policlinico, Milan, Italy; Department of Oncology and Hemato-Oncology, University of Milan, 20122, Milan, ItalyHematology Department, Fondazione IRCCS Cà Granda Ospedale Maggiore Policlinico, Milan, Italy; Department of Oncology and Hemato-Oncology, University of Milan, 20122, Milan, ItalyDepartment of Immunology, Genetics and Pathology, Uppsala University, Uppsala, SwedenDepartment of Zoophysiology, Institute of Biochemistry and Biology, University of Potsdam, GermanyVascular Biology Unit, IFOM ETS-The AIRC Institute of Molecular Oncology, Milan, Italy; Department of Immunology, Genetics and Pathology, Uppsala University, Uppsala, SwedenDepartment of Acute Brain and Cardiovascular Injury, Institute for Pharmacological Research Mario Negri IRCCS, Milan, ItalySummary: Background: Cerebral Cavernous Malformation (CCM) is a rare cerebrovascular disease, characterized by the presence of multiple vascular malformations that may result in intracerebral hemorrhages (ICHs), seizure(s), or focal neurological deficits (FND). Familial CCM (fCCM) is due to loss of function mutations in one of the three independent genes KRIT1 (CCM1), Malcavernin (CCM2), or Programmed Cell death 10 (PDCD10/CCM3). The aim of this study was to identify plasma protein biomarkers of fCCM to assess the severity of the disease and predict its progression. Methods: Here, we have investigated plasma samples derived from n = 71 symptomatic fCCM patients (40 female/31 male) and n = 17 healthy donors (HD) (9 female/8 male) of the Phase 1/2 Treat_CCM trial, using multiplexed protein profiling approaches. Findings: Biomarkers as sCD14 (p = 0.00409), LBP (p = 0.02911), CXCL4 (p = 0.038), ICAM-1 (p = 0.02013), ANG2 (p = 0.026), CCL5 (p = 0.00403), THBS1 (p = 0.0043), CRP (p = 0.0092), and HDL (p = 0.027), were significantly different in fCCM compared to HDs. Of note, sENG (p = 0.011), THBS1 (p = 0.011) and CXCL4 (p = 0.011), were correlated to CCM genotype. sROBO4 (p = 0.014), TM (p = 0.026) and CRP (p = 0.040) were able to predict incident adverse clinical events, such as ICH, FND or seizure. GDF-15, FLT3L, CXCL9, FGF-21 and CDCP1, were identified as predictors of the formation of new MRI-detectable lesions over 2-year follow-up. Furthermore, the functional relevance of ang2, thbs1, robo4 and cdcp1 markers was validated by zebrafish pre-clinical model of fCCM. Interpretation: Overall, our study identifies a set of biochemical parameters to predict CCM progression, suggesting biological interpretations and potential therapeutic approaches to CCM disease. Funding: Italian Medicines Agency, Associazione Italiana per la Ricerca sul Cancro (AIRC), ERC, Leducq Transatlantic Network of Excellence, Swedish Research Council.http://www.sciencedirect.com/science/article/pii/S2352396423004802Familial cerebral cavernous malformationVascular biologyBiomarkersProteomics |
| spellingShingle | Francesca Lazzaroni Jennifer M.T.A. Meessen Ying Sun Silvia Lanfranconi Elisa Scola Quintino Giorgio D'Alessandris Laura Tassi Maria Rita Carriero Marco Castori Silvia Marino Adriana Blanda Enrico B. Nicolis Deborah Novelli Roberta Calabrese Nicolò M. Agnelli Barbara Bottazzi Roberto Leone Selene Mazzola Silvia Besana Carlotta Catozzi Luigi Nezi Maria G. Lampugnani Matteo Malinverno Nastasja Grdseloff Claudia J. Rödel Behnam Rezai Jahromi Niccolò Bolli Francesco Passamonti Peetra U. Magnusson Salim Abdelilah-Seyfried Elisabetta Dejana Roberto Latini Circulating biomarkers in familial cerebral cavernous malformationResearch in context EBioMedicine Familial cerebral cavernous malformation Vascular biology Biomarkers Proteomics |
| title | Circulating biomarkers in familial cerebral cavernous malformationResearch in context |
| title_full | Circulating biomarkers in familial cerebral cavernous malformationResearch in context |
| title_fullStr | Circulating biomarkers in familial cerebral cavernous malformationResearch in context |
| title_full_unstemmed | Circulating biomarkers in familial cerebral cavernous malformationResearch in context |
| title_short | Circulating biomarkers in familial cerebral cavernous malformationResearch in context |
| title_sort | circulating biomarkers in familial cerebral cavernous malformationresearch in context |
| topic | Familial cerebral cavernous malformation Vascular biology Biomarkers Proteomics |
| url | http://www.sciencedirect.com/science/article/pii/S2352396423004802 |
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