Histamine signaling and metabolism identify potential biomarkers and therapies for lymphangioleiomyomatosis

Herranz, Carmen; Mateo, Francesca; Baiges, Alexandra; Ruiz de Garibay, Gorka; Junza, Alexandra; Johnson, Simon R.; Miller, Suzanne; García, Nadia; Capellades, Jordi; Gómez, Antonio; Vidal, August; Palomero, Luis; Espín, Roderic; Extremera, Ana I.; Blommaert, Eline; Revilla-López, Eva; Sáez, Berta; Gómez-Ollés, Susana; Ancochea, Julio; Valenzuela, Claudia; Alonso, Tamara; Ussetti, Piedad; Laporta, Rosalía; Xaubet, Antoni; Rodríguez-Portal, José A.; Montes-Worboys, Ana; Machahua, Carlos; Bordas, Jaume; Menéndez, Javier A.; Cruzado, Josep M.; Guiteras, Roser; Bontoux, Christophe; La Motta, Concettina; Noguera-Castells, Aleix; Mancino, Mario; Lastra, Enrique; Rigo-Bonnin, Raúl; Perales, José C.; Viñals, Francesc; Lahiguera, Álvaro; Zhang, Xiaohu; Cuadras, Daniel; Moorsel, Coline H. M. van; Vis, Joanne J. van der; Quanjel, Marian J. R.; Filippakis, Harilaos; Hakem, Razq; Gorrini, Chiara; Ferrer, Marc; Ugun-Klusek, Aslihan; Billett, Ellen; Radzikowska, Elżbieta; Casanova, Álvaro; Molina-Molina, María; Román, Antonio; Yanes, Óscar; Pujana, Miguel Ángel

Histamine signaling and metabolism identify potential biomarkers and therapies for lymphangioleiomyomatosis

Inhibition of mTOR is the standard of care for lymphangioleiomyomatosis (LAM). However, this therapy has variable tolerability and some patients show progressive decline of lung function despite treatment. LAM diagnosis and monitoring can also be challenging due to the heterogeneity of symptoms and...

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Authors:	Herranz, Carmen, Mateo, Francesca, Baiges, Alexandra, Ruiz de Garibay, Gorka, Junza, Alexandra, Johnson, Simon R., Miller, Suzanne, García, Nadia, Capellades, Jordi, Gómez, Antonio, Vidal, August, Palomero, Luis, Espín, Roderic, Extremera, Ana I., Blommaert, Eline, Revilla-López, Eva, Sáez, Berta, Gómez-Ollés, Susana, Ancochea, Julio, Valenzuela, Claudia, Alonso, Tamara, Ussetti, Piedad, Laporta, Rosalía, Xaubet, Antoni, Rodríguez-Portal, José A., Montes-Worboys, Ana, Machahua, Carlos, Bordas, Jaume, Menéndez, Javier A., Cruzado, Josep M., Guiteras, Roser, Bontoux, Christophe, La Motta, Concettina, Noguera-Castells, Aleix, Mancino, Mario, Lastra, Enrique, Rigo-Bonnin, Raúl, Perales, José C., Viñals, Francesc, Lahiguera, Álvaro, Zhang, Xiaohu, Cuadras, Daniel, Moorsel, Coline H. M. van, Vis, Joanne J. van der, Quanjel, Marian J. R., Filippakis, Harilaos, Hakem, Razq, Gorrini, Chiara, Ferrer, Marc, Ugun-Klusek, Aslihan, Billett, Ellen, Radzikowska, Elżbieta, Casanova, Álvaro, Molina-Molina, María, Román, Antonio, Yanes, Óscar, Pujana, Miguel Ángel
Format:	article
Status:	Published version
Publication Date:	2021
Country:	España
Institution:	Consejo Superior de Investigaciones Científicas (CSIC)
Repository:	DIGITAL.CSIC. Repositorio Institucional del CSIC
OAI Identifier:	oai:digital.csic.es:10261/265901
Online Access:	http://hdl.handle.net/10261/265901
Access Level:	Open access
Keyword:	Biomarkers Histamine Lymphangioleiomyomatosis mTOR Therapy

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spelling	Histamine signaling and metabolism identify potential biomarkers and therapies for lymphangioleiomyomatosisHerranz, CarmenMateo, FrancescaBaiges, AlexandraRuiz de Garibay, GorkaJunza, AlexandraJohnson, Simon R.Miller, SuzanneGarcía, NadiaCapellades, JordiGómez, AntonioVidal, AugustPalomero, LuisEspín, RodericExtremera, Ana I.Blommaert, ElineRevilla-López, EvaSáez, BertaGómez-Ollés, SusanaAncochea, JulioValenzuela, ClaudiaAlonso, TamaraUssetti, PiedadLaporta, RosalíaXaubet, AntoniRodríguez-Portal, José A.Montes-Worboys, AnaMachahua, CarlosBordas, JaumeMenéndez, Javier A.Cruzado, Josep M.Guiteras, RoserBontoux, ChristopheLa Motta, ConcettinaNoguera-Castells, AleixMancino, MarioLastra, EnriqueRigo-Bonnin, RaúlPerales, José C.Viñals, FrancescLahiguera, ÁlvaroZhang, XiaohuCuadras, DanielMoorsel, Coline H. M. vanVis, Joanne J. van derQuanjel, Marian J. R.Filippakis, HarilaosHakem, RazqGorrini, ChiaraFerrer, MarcUgun-Klusek, AslihanBillett, EllenRadzikowska, ElżbietaCasanova, ÁlvaroMolina-Molina, MaríaRomán, AntonioYanes, ÓscarPujana, Miguel ÁngelBiomarkersHistamineLymphangioleiomyomatosismTORTherapyInhibition of mTOR is the standard of care for lymphangioleiomyomatosis (LAM). However, this therapy has variable tolerability and some patients show progressive decline of lung function despite treatment. LAM diagnosis and monitoring can also be challenging due to the heterogeneity of symptoms and insufficiency of non-invasive tests. Here, we propose monoamine-derived biomarkers that provide preclinical evidence for novel therapeutic approaches. The major histamine-derived metabolite methylimidazoleacetic acid (MIAA) is relatively more abundant in LAM plasma, and MIAA values are independent of VEGF-D. Higher levels of histamine are associated with poorer lung function and greater disease burden. Molecular and cellular analyses, and metabolic profiling confirmed active histamine signaling and metabolism. LAM tumorigenesis is reduced using approved drugs targeting monoamine oxidases A/B (clorgyline and rasagiline) or histamine H1 receptor (loratadine), and loratadine synergizes with rapamycin. Depletion of Maoa or Hrh1 expression, and administration of an L-histidine analog, or a low L-histidine diet, also reduce LAM tumorigenesis. These findings extend our knowledge of LAM biology and suggest possible ways of improving disease management.This research was supported by AELAM, The LAM Foundation (Seed Grant 2019), Instituto de Salud Carlos III grants PI15/00854, PI18/01029, and ICI19/00047 (co-funded by European Regional Development Fund (ERDF), a way to build Europe), Generalitat de Catalunya SGR grants 2014-364 and 2017-449, the CERCA Program, and ZonMW-TopZorg grant 842002003. C.L.M. acknowledges the financial support (PRA-2017-51 project) of the University of Pisa. A.U.K. is supported by Nottingham Trent University’s Independent Fellowship Scheme.Peer reviewedEMBO PressAsociación Española de LinfangioleiomiomatosisInstituto de Salud Carlos IIIEuropean CommissionGeneralitat de CatalunyaUniversità di PisaNottingham Trent UniversityConsejo Superior de Investigaciones Científicas [https://ror.org/02gfc7t72]202220222021info:eu-repo/semantics/articlehttp://purl.org/coar/resource_type/c_6501Publisher's versioninfo:eu-repo/semantics/publishedVersionapplication/pdfhttp://hdl.handle.net/10261/265901reponame:DIGITAL.CSIC. Repositorio Institucional del CSICinstname:Consejo Superior de Investigaciones Científicas (CSIC)Ingléshttps://doi.org/10.15252/emmm.202113929Síinfo:eu-repo/semantics/openAccessoai:digital.csic.es:10261/2659012026-05-22T06:33:51Z
dc.title.none.fl_str_mv	Histamine signaling and metabolism identify potential biomarkers and therapies for lymphangioleiomyomatosis
title	Histamine signaling and metabolism identify potential biomarkers and therapies for lymphangioleiomyomatosis
spellingShingle	Histamine signaling and metabolism identify potential biomarkers and therapies for lymphangioleiomyomatosis Herranz, Carmen Biomarkers Histamine Lymphangioleiomyomatosis mTOR Therapy
title_short	Histamine signaling and metabolism identify potential biomarkers and therapies for lymphangioleiomyomatosis
title_full	Histamine signaling and metabolism identify potential biomarkers and therapies for lymphangioleiomyomatosis
title_fullStr	Histamine signaling and metabolism identify potential biomarkers and therapies for lymphangioleiomyomatosis
title_full_unstemmed	Histamine signaling and metabolism identify potential biomarkers and therapies for lymphangioleiomyomatosis
title_sort	Histamine signaling and metabolism identify potential biomarkers and therapies for lymphangioleiomyomatosis
dc.creator.none.fl_str_mv	Herranz, Carmen Mateo, Francesca Baiges, Alexandra Ruiz de Garibay, Gorka Junza, Alexandra Johnson, Simon R. Miller, Suzanne García, Nadia Capellades, Jordi Gómez, Antonio Vidal, August Palomero, Luis Espín, Roderic Extremera, Ana I. Blommaert, Eline Revilla-López, Eva Sáez, Berta Gómez-Ollés, Susana Ancochea, Julio Valenzuela, Claudia Alonso, Tamara Ussetti, Piedad Laporta, Rosalía Xaubet, Antoni Rodríguez-Portal, José A. Montes-Worboys, Ana Machahua, Carlos Bordas, Jaume Menéndez, Javier A. Cruzado, Josep M. Guiteras, Roser Bontoux, Christophe La Motta, Concettina Noguera-Castells, Aleix Mancino, Mario Lastra, Enrique Rigo-Bonnin, Raúl Perales, José C. Viñals, Francesc Lahiguera, Álvaro Zhang, Xiaohu Cuadras, Daniel Moorsel, Coline H. M. van Vis, Joanne J. van der Quanjel, Marian J. R. Filippakis, Harilaos Hakem, Razq Gorrini, Chiara Ferrer, Marc Ugun-Klusek, Aslihan Billett, Ellen Radzikowska, Elżbieta Casanova, Álvaro Molina-Molina, María Román, Antonio Yanes, Óscar Pujana, Miguel Ángel
author	Herranz, Carmen
author_facet	Herranz, Carmen Mateo, Francesca Baiges, Alexandra Ruiz de Garibay, Gorka Junza, Alexandra Johnson, Simon R. Miller, Suzanne García, Nadia Capellades, Jordi Gómez, Antonio Vidal, August Palomero, Luis Espín, Roderic Extremera, Ana I. Blommaert, Eline Revilla-López, Eva Sáez, Berta Gómez-Ollés, Susana Ancochea, Julio Valenzuela, Claudia Alonso, Tamara Ussetti, Piedad Laporta, Rosalía Xaubet, Antoni Rodríguez-Portal, José A. Montes-Worboys, Ana Machahua, Carlos Bordas, Jaume Menéndez, Javier A. Cruzado, Josep M. Guiteras, Roser Bontoux, Christophe La Motta, Concettina Noguera-Castells, Aleix Mancino, Mario Lastra, Enrique Rigo-Bonnin, Raúl Perales, José C. Viñals, Francesc Lahiguera, Álvaro Zhang, Xiaohu Cuadras, Daniel Moorsel, Coline H. M. van Vis, Joanne J. van der Quanjel, Marian J. R. Filippakis, Harilaos Hakem, Razq Gorrini, Chiara Ferrer, Marc Ugun-Klusek, Aslihan Billett, Ellen Radzikowska, Elżbieta Casanova, Álvaro Molina-Molina, María Román, Antonio Yanes, Óscar Pujana, Miguel Ángel
author_role	author
author2	Mateo, Francesca Baiges, Alexandra Ruiz de Garibay, Gorka Junza, Alexandra Johnson, Simon R. Miller, Suzanne García, Nadia Capellades, Jordi Gómez, Antonio Vidal, August Palomero, Luis Espín, Roderic Extremera, Ana I. Blommaert, Eline Revilla-López, Eva Sáez, Berta Gómez-Ollés, Susana Ancochea, Julio Valenzuela, Claudia Alonso, Tamara Ussetti, Piedad Laporta, Rosalía Xaubet, Antoni Rodríguez-Portal, José A. Montes-Worboys, Ana Machahua, Carlos Bordas, Jaume Menéndez, Javier A. Cruzado, Josep M. Guiteras, Roser Bontoux, Christophe La Motta, Concettina Noguera-Castells, Aleix Mancino, Mario Lastra, Enrique Rigo-Bonnin, Raúl Perales, José C. Viñals, Francesc Lahiguera, Álvaro Zhang, Xiaohu Cuadras, Daniel Moorsel, Coline H. M. van Vis, Joanne J. van der Quanjel, Marian J. R. Filippakis, Harilaos Hakem, Razq Gorrini, Chiara Ferrer, Marc Ugun-Klusek, Aslihan Billett, Ellen Radzikowska, Elżbieta Casanova, Álvaro Molina-Molina, María Román, Antonio Yanes, Óscar Pujana, Miguel Ángel
author2_role	author author author author author author author author author author author author author author author author author author author author author author author author author author author author author author author author author author author author author author author author author author author author author author author author author author author author author author author author
dc.contributor.none.fl_str_mv	Asociación Española de Linfangioleiomiomatosis Instituto de Salud Carlos III European Commission Generalitat de Catalunya Università di Pisa Nottingham Trent University Consejo Superior de Investigaciones Científicas [https://ror.org/02gfc7t72]
dc.subject.none.fl_str_mv	Biomarkers Histamine Lymphangioleiomyomatosis mTOR Therapy
topic	Biomarkers Histamine Lymphangioleiomyomatosis mTOR Therapy
description	Inhibition of mTOR is the standard of care for lymphangioleiomyomatosis (LAM). However, this therapy has variable tolerability and some patients show progressive decline of lung function despite treatment. LAM diagnosis and monitoring can also be challenging due to the heterogeneity of symptoms and insufficiency of non-invasive tests. Here, we propose monoamine-derived biomarkers that provide preclinical evidence for novel therapeutic approaches. The major histamine-derived metabolite methylimidazoleacetic acid (MIAA) is relatively more abundant in LAM plasma, and MIAA values are independent of VEGF-D. Higher levels of histamine are associated with poorer lung function and greater disease burden. Molecular and cellular analyses, and metabolic profiling confirmed active histamine signaling and metabolism. LAM tumorigenesis is reduced using approved drugs targeting monoamine oxidases A/B (clorgyline and rasagiline) or histamine H1 receptor (loratadine), and loratadine synergizes with rapamycin. Depletion of Maoa or Hrh1 expression, and administration of an L-histidine analog, or a low L-histidine diet, also reduce LAM tumorigenesis. These findings extend our knowledge of LAM biology and suggest possible ways of improving disease management.
publishDate	2021
dc.date.none.fl_str_mv	2021 2022 2022
dc.type.none.fl_str_mv	info:eu-repo/semantics/article http://purl.org/coar/resource_type/c_6501 Publisher's version info:eu-repo/semantics/publishedVersion
format	article
status_str	publishedVersion
dc.identifier.none.fl_str_mv	http://hdl.handle.net/10261/265901
url	http://hdl.handle.net/10261/265901
dc.language.none.fl_str_mv	Inglés
language_invalid_str_mv	Inglés
dc.relation.none.fl_str_mv	https://doi.org/10.15252/emmm.202113929 Sí
dc.rights.none.fl_str_mv	info:eu-repo/semantics/openAccess
eu_rights_str_mv	openAccess
dc.format.none.fl_str_mv	application/pdf
dc.publisher.none.fl_str_mv	EMBO Press
publisher.none.fl_str_mv	EMBO Press
dc.source.none.fl_str_mv	reponame:DIGITAL.CSIC. Repositorio Institucional del CSIC instname:Consejo Superior de Investigaciones Científicas (CSIC)
instname_str	Consejo Superior de Investigaciones Científicas (CSIC)
reponame_str	DIGITAL.CSIC. Repositorio Institucional del CSIC
collection	DIGITAL.CSIC. Repositorio Institucional del CSIC
repository.name.fl_str_mv
repository.mail.fl_str_mv
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score	15,812429

Histamine signaling and metabolism identify potential biomarkers and therapies for lymphangioleiomyomatosis

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