Inter- and intra-tumoral ALDH1 heterogeneity in breast cancer identifies therapeutic opportunities for ALDH1A-specific inhibitors
Pequerul Pavón, Raquel (Universitat Autònoma de Barcelona. Departament de Bioquímica i de Biologia Molecular)
Constantinescu, Andrada (Advanced BioDesign)
Janji, Bassam (Luxembourg Institute of Health (LIH))
Kumar, Akinchan (Luxembourg Institute of Health (LIH))
Baier, Céline (Advanced BioDesign)
Manosalva, Iris (Aix-Marseille University)
Parés i Casasampera, Xavier (Universitat Autònoma de Barcelona. Departament de Bioquímica i de Biologia Molecular)
Palacios, Oscar (Universitat Autònoma de Barcelona. Departament de Química)
Spicuglia, Salvatore (Aix-Marseille University)
Colignon, Delphine (Université de Lyon 1)
Berrou, Axelle (Nantes University)
Fournet, Guy (Nantes University)
Berchard, Paul (Advanced BioDesign)
Martin, Guillaume (Advanced BioDesign)
Ceylan, Ismail (Advanced BioDesign)
Rebollido-Rios, Rocio (University of Cologne)
Farrés, Jaume (Mayo Clinic (Rochester, Estats Units d'Amèrica))
Perez-Alea, Mileidys (Advanced BioDesign)

Fecha:	2025
Resumen:	Basal-like breast cancer is an aggressive subtype with limited therapeutic options. Here, transcriptomic analysis of public datasets suggested distinct subtype- and cell-specific expression patterns of ALDH1A isoforms in breast tumors, with ALDH1A3 predominantly expressed in the epithelial cells of basal-like tumors, whereas ALDH1A2 and ALDH1A1 were enriched in stromal and immune-associated subpopulations. High expression of ALDH1A3 and ALDH1A2, but not ALDH1A1, is associated with poor prognosis in high-grade, lymph-node-positive tumors. To evaluate therapeutic targeting, we developed ABD0171, an irreversible, selective ALDH1A3 inhibitor with additional ALDH1A1 activity. ABD0171 disrupted key oncogenic pathways, including IL6/JAK/STAT3, tPA, and Src/FAK, resulting in robust antitumor and antimetastatic effects in vitro and in vivo, with a favorable safety profile. These findings establish ALDH1A3 as a therapeutic target in breast cancers with epithelial-basal traits and validate ABD0171 as a promising clinical candidate to address current treatment challenges.
Ayudas:	Agencia Estatal de Investigación PID2020-119424RB-I00
Derechos:	Aquest document està subjecte a una llicència d'ús Creative Commons. Es permet la reproducció total o parcial, la distribució, i la comunicació pública de l'obra, sempre que no sigui amb finalitats comercials, i sempre que es reconegui l'autoria de l'obra original. No es permet la creació d'obres derivades.
Lengua:	Anglès
Documento:	Article ; recerca ; Versió acceptada per publicar
Materia:	Bulk and single-cell transcriptomic analysis ; Prognostic biomarker ; Chemoresistance ; Isoform-specific inhibition ; TNBC ; Triple-negative breast cancer ; Breast cancer ; ALDH1A3 ; ALDH1A2 ; ALDH ; Aldehyde dehydrogenase
Publicado en:	Cell Chemical Biology, Vol. 32 Núm. 10 (October 2025) , p. 1260-1278.e12, ISSN 1879-1301

DOI: 10.1016/j.chembiol.2025.09.003
PMID: 41033308

Disponible a partir de: 2026-10-31 Postprint

El registro aparece en las colecciones:
Artículos > Artículos de investigación
Artículos > Artículos publicados