Histamine signaling and metabolism identify potential biomarkers and therapies for lymphangioleiomyomatosis.
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ICR Authors
Authors
Herranz, C
Mateo, F
Baiges, A
Ruiz de Garibay, G
Junza, A
Johnson, SR
Miller, S
García, N
Capellades, J
Gómez, A
Vidal, A
Palomero, L
Espín, R
Extremera, AI
Blommaert, E
Revilla-López, E
Saez, B
Gómez-Ollés, S
Ancochea, J
Valenzuela, C
Alonso, T
Ussetti, P
Laporta, R
Xaubet, A
Rodríguez-Portal, JA
Montes-Worboys, A
Machahua, C
Bordas, J
Menendez, JA
Cruzado, JM
Guiteras, R
Bontoux, C
La Motta, C
Noguera-Castells, A
Mancino, M
Lastra, E
Rigo-Bonnin, R
Perales, JC
Viñals, F
Lahiguera, A
Zhang, X
Cuadras, D
van Moorsel, CHM
van der Vis, JJ
Quanjel, MJR
Filippakis, H
Hakem, R
Gorrini, C
Ferrer, M
Ugun-Klusek, A
Billett, E
Radzikowska, E
Casanova, Á
Molina-Molina, M
Roman, A
Yanes, O
Pujana, MA
Mateo, F
Baiges, A
Ruiz de Garibay, G
Junza, A
Johnson, SR
Miller, S
García, N
Capellades, J
Gómez, A
Vidal, A
Palomero, L
Espín, R
Extremera, AI
Blommaert, E
Revilla-López, E
Saez, B
Gómez-Ollés, S
Ancochea, J
Valenzuela, C
Alonso, T
Ussetti, P
Laporta, R
Xaubet, A
Rodríguez-Portal, JA
Montes-Worboys, A
Machahua, C
Bordas, J
Menendez, JA
Cruzado, JM
Guiteras, R
Bontoux, C
La Motta, C
Noguera-Castells, A
Mancino, M
Lastra, E
Rigo-Bonnin, R
Perales, JC
Viñals, F
Lahiguera, A
Zhang, X
Cuadras, D
van Moorsel, CHM
van der Vis, JJ
Quanjel, MJR
Filippakis, H
Hakem, R
Gorrini, C
Ferrer, M
Ugun-Klusek, A
Billett, E
Radzikowska, E
Casanova, Á
Molina-Molina, M
Roman, A
Yanes, O
Pujana, MA
Document Type
Journal Article
Date
2021-09-07
Date Accepted
2021-07-21
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.
Citation
EMBO molecular medicine, 2021, pp. e13929 - ?
Source Title
Publisher
SPRINGERNATURE
ISSN
1757-4676
eISSN
1757-4684
Research Team
Paediatric Solid Tumour Biology and Therapeutics
Paediatric Solid Tumour Biology and Therapeutics
Paediatric Solid Tumour Biology and Therapeutics