EMBO Molecular Medicine (Aug 2021)
Histamine signaling and metabolism identify potential biomarkers and therapies for lymphangioleiomyomatosis
- Carmen Herranz,
- Francesca Mateo,
- Alexandra Baiges,
- Gorka Ruiz de Garibay,
- Alexandra Junza,
- Simon R Johnson,
- Suzanne Miller,
- Nadia García,
- Jordi Capellades,
- Antonio Gómez,
- August Vidal,
- Luis Palomero,
- Roderic Espín,
- Ana I Extremera,
- Eline Blommaert,
- Eva Revilla‐López,
- Berta Saez,
- Susana Gómez‐Ollés,
- Julio Ancochea,
- Claudia Valenzuela,
- Tamara Alonso,
- Piedad Ussetti,
- Rosalía Laporta,
- Antoni Xaubet,
- José A Rodríguez‐Portal,
- Ana Montes‐Worboys,
- Carlos Machahua,
- Jaume Bordas,
- Javier A Menendez,
- Josep M Cruzado,
- Roser Guiteras,
- Christophe Bontoux,
- Concettina La Motta,
- Aleix Noguera‐Castells,
- Mario Mancino,
- Enrique Lastra,
- Raúl Rigo‐Bonnin,
- Jose C Perales,
- Francesc Viñals,
- Alvaro Lahiguera,
- Xiaohu Zhang,
- Daniel Cuadras,
- Coline H M van Moorsel,
- Joanne J van der Vis,
- Marian J R Quanjel,
- Harilaos Filippakis,
- Razq Hakem,
- Chiara Gorrini,
- Marc Ferrer,
- Aslihan Ugun‐Klusek,
- Ellen Billett,
- Elżbieta Radzikowska,
- Álvaro Casanova,
- María Molina‐Molina,
- Antonio Roman,
- Oscar Yanes,
- Miquel A Pujana
Affiliations
- Carmen Herranz
- ProCURE, Catalan Institute of Oncology, Oncobell, Bellvitge Institute for Biomedical Research (IDIBELL), L’Hospitalet del Llobregat
- Francesca Mateo
- ProCURE, Catalan Institute of Oncology, Oncobell, Bellvitge Institute for Biomedical Research (IDIBELL), L’Hospitalet del Llobregat
- Alexandra Baiges
- ProCURE, Catalan Institute of Oncology, Oncobell, Bellvitge Institute for Biomedical Research (IDIBELL), L’Hospitalet del Llobregat
- Gorka Ruiz de Garibay
- ProCURE, Catalan Institute of Oncology, Oncobell, Bellvitge Institute for Biomedical Research (IDIBELL), L’Hospitalet del Llobregat
- Alexandra Junza
- Department of Electronic Engineering, Institute of Health Research Pere Virgili (IIPSV), University Rovira i Virgili
- Simon R Johnson
- National Centre for Lymphangioleiomyomatosis, Nottingham University Hospitals NHS Trust, Nottinghamshire, Division of Respiratory Medicine, University of Nottingham
- Suzanne Miller
- National Centre for Lymphangioleiomyomatosis, Nottingham University Hospitals NHS Trust, Nottinghamshire, Division of Respiratory Medicine, University of Nottingham
- Nadia García
- ProCURE, Catalan Institute of Oncology, Oncobell, Bellvitge Institute for Biomedical Research (IDIBELL), L’Hospitalet del Llobregat
- Jordi Capellades
- Department of Electronic Engineering, Institute of Health Research Pere Virgili (IIPSV), University Rovira i Virgili
- Antonio Gómez
- Centre for Genomic Regulation, Barcelona Institute of Science and Technology
- August Vidal
- Department of Pathology, University Hospital of Bellvitge, Oncobell, IDIBELL, L’Hospitalet del Llobregat
- Luis Palomero
- ProCURE, Catalan Institute of Oncology, Oncobell, Bellvitge Institute for Biomedical Research (IDIBELL), L’Hospitalet del Llobregat
- Roderic Espín
- ProCURE, Catalan Institute of Oncology, Oncobell, Bellvitge Institute for Biomedical Research (IDIBELL), L’Hospitalet del Llobregat
- Ana I Extremera
- ProCURE, Catalan Institute of Oncology, Oncobell, Bellvitge Institute for Biomedical Research (IDIBELL), L’Hospitalet del Llobregat
- Eline Blommaert
- ProCURE, Catalan Institute of Oncology, Oncobell, Bellvitge Institute for Biomedical Research (IDIBELL), L’Hospitalet del Llobregat
- Eva Revilla‐López
- Lung Transplant Unit, Pneumology Service, Lymphangioleiomyomatosis Clinic, Vall d’Hebron University Hospital
- Berta Saez
- Lung Transplant Unit, Pneumology Service, Lymphangioleiomyomatosis Clinic, Vall d’Hebron University Hospital
- Susana Gómez‐Ollés
- Lung Transplant Unit, Pneumology Service, Lymphangioleiomyomatosis Clinic, Vall d’Hebron University Hospital
- Julio Ancochea
- Pneumology Service, La Princesa Research Institute, University Hospital La Princesa
- Claudia Valenzuela
- Pneumology Service, La Princesa Research Institute, University Hospital La Princesa
- Tamara Alonso
- Pneumology Service, La Princesa Research Institute, University Hospital La Princesa
- Piedad Ussetti
- Pneumology Service, University Hospital Clínica Puerta del Hierro, Majadahonda
- Rosalía Laporta
- Pneumology Service, University Hospital Clínica Puerta del Hierro, Majadahonda
- Antoni Xaubet
- Pneumology Service, Hospital Clínic de Barcelona
- José A Rodríguez‐Portal
- Medical‐Surgical Unit of Respiratory Diseases, Institute of Biomedicine of Seville (IBiS), University Hospital Virgen del Rocío
- Ana Montes‐Worboys
- Biomedical Research Network Centre in Respiratory Diseases (CIBERES), Instituto de Salud Carlos III
- Carlos Machahua
- Biomedical Research Network Centre in Respiratory Diseases (CIBERES), Instituto de Salud Carlos III
- Jaume Bordas
- Biomedical Research Network Centre in Respiratory Diseases (CIBERES), Instituto de Salud Carlos III
- Javier A Menendez
- ProCURE, Catalan Institute of Oncology, Oncobell, Bellvitge Institute for Biomedical Research (IDIBELL), L’Hospitalet del Llobregat
- Josep M Cruzado
- Experimental Nephrology, Department of Clinical Sciences, University of Barcelona
- Roser Guiteras
- Experimental Nephrology, Department of Clinical Sciences, University of Barcelona
- Christophe Bontoux
- Department of Pathology, University Hospital Pitié‐Salpêtrière, Faculty of Medicine, University of Sorbonne
- Concettina La Motta
- Department of Pharmacy, University of Pisa
- Aleix Noguera‐Castells
- Biomedical Research Institute “August Pi i Sunyer” (IDIBAPS), Department of Medicine, University of Barcelona
- Mario Mancino
- Biomedical Research Institute “August Pi i Sunyer” (IDIBAPS), Department of Medicine, University of Barcelona
- Enrique Lastra
- Genetic Counseling Unit, Department of Medical Oncology, University Hospital of Burgos
- Raúl Rigo‐Bonnin
- Clinical Laboratory, University Hospital of Bellvitge, IDIBELL, L'Hospitalet de Llobregat
- Jose C Perales
- Department of Physiological Science II, University of Barcelona
- Francesc Viñals
- ProCURE, Catalan Institute of Oncology, Oncobell, Bellvitge Institute for Biomedical Research (IDIBELL), L’Hospitalet del Llobregat
- Alvaro Lahiguera
- ProCURE, Catalan Institute of Oncology, Oncobell, Bellvitge Institute for Biomedical Research (IDIBELL), L’Hospitalet del Llobregat
- Xiaohu Zhang
- National Center for Advancing Translational Sciences (NCATS), National Institute of Health (NIH)
- Daniel Cuadras
- Statistics Department, Foundation Sant Joan de Déu
- Coline H M van Moorsel
- Interstitial Lung Disease (ILD) Center of Excellence, St. Antonius Hospital
- Joanne J van der Vis
- Interstitial Lung Disease (ILD) Center of Excellence, St. Antonius Hospital
- Marian J R Quanjel
- Interstitial Lung Disease (ILD) Center of Excellence, St. Antonius Hospital
- Harilaos Filippakis
- Pulmonary and Critical Care Medicine, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School
- Razq Hakem
- Princess Margaret Cancer Centre, University Health Network, Department of Medical Biophysics, University of Toronto
- Chiara Gorrini
- Princess Margaret Hospital, The Campbell Family Institute for Breast Cancer Research, Ontario Cancer Institute, University Health Network
- Marc Ferrer
- National Center for Advancing Translational Sciences (NCATS), National Institute of Health (NIH)
- Aslihan Ugun‐Klusek
- Centre for Health, Ageing and Understanding Disease (CHAUD), School of Science and Technology, Nottingham Trent University
- Ellen Billett
- Centre for Health, Ageing and Understanding Disease (CHAUD), School of Science and Technology, Nottingham Trent University
- Elżbieta Radzikowska
- Department of Lung Diseases III, National Tuberculosis and Lung Disease Research Institute
- Álvaro Casanova
- Pneumology Service, University Hospital of Henares, University Francisco de Vitoria, Coslada
- María Molina‐Molina
- Biomedical Research Network Centre in Respiratory Diseases (CIBERES), Instituto de Salud Carlos III
- Antonio Roman
- Lung Transplant Unit, Pneumology Service, Lymphangioleiomyomatosis Clinic, Vall d’Hebron University Hospital
- Oscar Yanes
- Department of Electronic Engineering, Institute of Health Research Pere Virgili (IIPSV), University Rovira i Virgili
- Miquel A Pujana
- ProCURE, Catalan Institute of Oncology, Oncobell, Bellvitge Institute for Biomedical Research (IDIBELL), L’Hospitalet del Llobregat
- DOI
- https://doi.org/10.15252/emmm.202113929
- Journal volume & issue
-
Vol. 13,
no. 9
pp. 1 – 21
Abstract
Abstract 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.
Keywords
