Histamine signaling and metabolism identify potential biomarkers and therapies for lymphangioleiomyomatosis.

Joanne J van der Vis, 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, Javier A Menendez, 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, Eline Blommaert, 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, Carmen Herranz, 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

Journal: EMBO molecular medicine 2021;13(9):e13929

PMID: 34378323

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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.

Address: ProCURE, Catalan Institute of Oncology, Oncobell, Bellvitge Institute for Biomedical Research (IDIBELL), L'Hospitalet del Llobregat, Barcelona, Spain.; Department of Electronic Engineering, Institute of Health Research Pere Virgili (IIPSV), University Rovira i Virgili, Tarragona, Spain.; Biomedical Research Network Centre in Diabetes and Associated Metabolic Diseases (CIBERDEM), Instituto de Salud Carlos III, Madrid, Spain.; National Centre for Lymphangioleiomyomatosis, Nottingham University Hospitals NHS Trust, Nottinghamshire, Division of Respiratory Medicine, University of Nottingham, Nottingham, UK.; Centre for Genomic Regulation, Barcelona Institute of Science and Technology, Barcelona, Spain.; Department of Pathology, University Hospital of Bellvitge, Oncobell, IDIBELL, L'Hospitalet del Llobregat, Barcelona, Spain.; CIBER on Cancer (CIBERONC), Instituto de Salud Carlos III, Madrid, Spain.; Lung Transplant Unit, Pneumology Service, Lymphangioleiomyomatosis Clinic, Vall d'Hebron University Hospital, Barcelona, Spain.; Pneumology Service, La Princesa Research Institute, University Hospital La Princesa, Madrid, Spain.; Pneumology Service, University Hospital Clínica Puerta del Hierro, Majadahonda, Madrid, Spain.; Pneumology Service, Hospital Clínic de Barcelona, Barcelona, Spain.; Medical-Surgical Unit of Respiratory Diseases, Institute of Biomedicine of Seville (IBiS), University Hospital Virgen del Rocío, Seville, Spain.; Biomedical Research Network Centre in Respiratory Diseases (CIBERES), Instituto de Salud Carlos III, Madrid, Spain.; Interstitial Lung Disease Unit, Department of Respiratory Medicine, University Hospital of Bellvitge, IDIBELL, L'Hospitalet del Llobregat, Barcelona, Spain.; Experimental Nephrology, Department of Clinical Sciences, University of Barcelona, Barcelona, Spain.; Department of Nephrology, University Hospital of Bellvitge, IDIBELL, L'Hospitalet del Llobregat, Barcelona, Spain.; Department of Pathology, University Hospital Pitié-Salpêtrière, Faculty of Medicine, University of Sorbonne, Paris, France.; Department of Pharmacy, University of Pisa, Pisa, Italy.; Biomedical Research Institute "August Pi i Sunyer" (IDIBAPS), Department of Medicine, University of Barcelona, Barcelona, Spain.; Genetic Counseling Unit, Department of Medical Oncology, University Hospital of Burgos, Burgos, Spain.; Clinical Laboratory, University Hospital of Bellvitge, IDIBELL, L'Hospitalet de Llobregat, Barcelona, Spain.; Department of Physiological Science II, University of Barcelona, Barcelona, Spain.; National Center for Advancing Translational Sciences (NCATS), National Institute of Health (NIH), Bethesda, MD, USA.; Statistics Department, Foundation Sant Joan de Déu, Esplugues, Spain.; Interstitial Lung Disease (ILD) Center of Excellence, St. Antonius Hospital, Nieuwegein, The Netherlands.; Pulmonary and Critical Care Medicine, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA.; Princess Margaret Cancer Centre, University Health Network, Department of Medical Biophysics, University of Toronto, Toronto, Ontario, Canada.; Princess Margaret Hospital, The Campbell Family Institute for Breast Cancer Research, Ontario Cancer Institute, University Health Network, Toronto, ON, Canada.; Centre for Health, Ageing and Understanding Disease (CHAUD), School of Science and Technology, Nottingham Trent University, Nottingham, UK.; Department of Lung Diseases III, National Tuberculosis and Lung Disease Research Institute, Warsaw, Poland.; Pneumology Service, University Hospital of Henares, University Francisco de Vitoria, Coslada, Madrid, Spain.

DOI: 10.15252/emmm.202113929