Fibroblastic aspartoacylase suppresses TGFβ-mediated responses and cancer progression
Metabolic reprogramming is a hallmark of cancer, and the field has predominantly focused on investigating metabolic alterations in tumour cells. However, the relevance, mechanism and consequences of metabolic adaptations in stromal cells remain understudied. Here, we identify aspartoacylase (ASPA) as a metabolic enzyme consistently repressed in tumour stroma and cancer-associated fibroblasts (CAFs). Importantly, we report a reciprocal crosstalk between ASPA and Transforming Growth Factor Beta (TGFβ) signalling that influences fibroblast behaviour. TGFβ suppresses ASPA expression in fibroblasts, whereas ASPA restrains TGFβ-dependent myofibroblast conversion, extracelullar cell matrix (ECM) remodelling, angiogenesis and pro-tumoral macrophage phenotypes. Analyses of human specimens revealed a strong negative prognostic value for ASPA in different tumour types, associated with TGFβ signalling levels and the generation of aggressive pro-tumoral responses. Our findings unveil ASPA expression in fibroblasts as a gatekeeper of TGFβ responses and activation in cancer progression. Metabolic alterations in tumor stromal cells remain to be understood. Here the authors identify Aspartoacylase (ASPA) as a metabolic enzyme consistently repressed in cancer-associated fibroblasts (CAFs) across different cancer types, highlighting reciprocal negative regulation between ASPA and TGFβ signalling in governing CAF activation and cancer progression.
Authors
- Massimiliano Mazzone (ORCID: https://orcid.org/0000-0001-8824-4015)
- Verónica Torrano (ORCID: https://orcid.org/0000-0002-4252-1977)
- Silvia Rivis (ORCID: https://orcid.org/0000-0002-0521-5751)
- Aida Santos-Martín
- Christian Frezza (ORCID: https://orcid.org/0000-0002-3293-7397)
- Arkaitz Carracedo (ORCID: https://orcid.org/0000-0001-5957-1260)
- Miguel Juliá (ORCID: https://orcid.org/0000-0002-4403-1840)
- Asís Palazón (ORCID: https://orcid.org/0000-0002-7172-7229)
- Sara Zanivan (ORCID: https://orcid.org/0000-0002-9880-9099)
- Isabel Mendizabal (ORCID: https://orcid.org/0000-0002-9018-3474)
- Carla Riera‐Domingo (ORCID: https://orcid.org/0000-0001-7277-234X)
- José I. López (ORCID: https://orcid.org/0000-0003-0842-5348)
- Onintza Carlevaris (ORCID: https://orcid.org/0000-0002-8616-6233)
- Patricia Carnicero
- Elisa Espinet (ORCID: https://orcid.org/0000-0002-0690-9878)
- Fernando Calvo (ORCID: https://orcid.org/0000-0001-8858-1185)
- Sara Cascais
- Maria Subijana
- Juan Manuel Falcón‐Pérez (ORCID: https://orcid.org/0000-0003-3133-0670)
- Leire Egia‐Mendikute (ORCID: https://orcid.org/0000-0002-6435-1219)
- Claudia Manini (ORCID: https://orcid.org/0000-0002-5823-7137)
- Noemí Eiró (ORCID: https://orcid.org/0000-0001-5840-4807)
- Joan Seoane (ORCID: https://orcid.org/0000-0002-6541-5974)
- Javier Rodríguez (ORCID: https://orcid.org/0000-0001-7467-8533)
- Roger R. Gomis (ORCID: https://orcid.org/0000-0001-6473-2858)
- Diana Cabrera (ORCID: https://orcid.org/0000-0001-8468-1875)
- Ana P. Vivancos (ORCID: https://orcid.org/0000-0003-2888-6512)
- Natalia Martín-Martín
- Sonia Fernández‐Ruiz
- Andreas Trumpp (ORCID: https://orcid.org/0000-0002-6212-3466)
- F Vizoso
- Ianire Astobiza (ORCID: https://orcid.org/0000-0002-7142-7066)
- Mireia Castillo-Martín (ORCID: https://orcid.org/0000-0001-8926-6013)
- Miguel Unda (ORCID: https://orcid.org/0000-0003-2849-9459)
- Emily J. Kay (ORCID: https://orcid.org/0000-0001-6706-4795)
- Aitziber Ugalde‐Olano
- Saioa Garcia‐Longarte (ORCID: https://orcid.org/0000-0001-5412-4234)
- Sofía Rey
- Cristina Viera
- Ainara Martínez
- Ana Loizaga‐Iriarte
- Mikel Pujana-Vaquerizo
- Jana R. Crespo
- Carmen Perez-Lopez
- Catalina Capó-Serra
- Carolina Ortiz-Sanz
- David Gonzalo
- Sebastian M. Van Liempd
Institutions
- Ikerbasque (ES)
- Champalimaud Foundation (PT)
- Institució Catalana de Recerca i Estudis Avançats (ES)
- Universidad de Cantabria (ES)
- The University of Texas MD Anderson Cancer Center (US)
- Consejo Superior de Investigaciones Científicas (ES)
- University of the Basque Country (ES)
- German Cancer Research Center (DE)
- Heidelberg University (DE)
- Institut d'Investigació Biomédica de Bellvitge (ES)
- BioCruces Health research Institute (ES)
- VIB-KU Leuven Center for Cancer Biology (BE)
- Hospital de Basurto (ES)
- Vall d'Hebron Institut de Recerca (ES)
- Instituto de Biomedicina y Biotecnología de Cantabria (ES)
- Fundación Hospital de Jove (ES)
- CIC bioGUNE (ES)
- Ospedale San Giovanni Bosco (IT)
- Institute for Research in Biomedicine (ES)
- Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (ES)
- Hospital de Cruces (ES)
- Cologne Excellence Cluster on Cellular Stress Responses in Aging Associated Diseases (DE)
- DKFZ-ZMBH Alliance (DE)
- Heidelberg Institute for Stem Cell Technology and Experimental Medicine (DE)
- Centro de Investigación Biomédica en Red de Cáncer (ES)
- Deutsches Konsortium für Translationale Krebsforschung (DE)
- University of Turin (IT)
- Universitat de Barcelona (ES)
- University of Glasgow (GB)
Publication Details
- Journal
- Nature Communications
- Published
- 2026-06-16
- DOI
- https://doi.org/10.1038/s41467-026-73002-6
- Primary Topic
- Cancer, Hypoxia, and Metabolism
- Type
- article
- Field-Weighted Citation Impact
- 0.00
Funders
- AstraZeneca
- Alexander von Humboldt-Stiftung
- Fundación BBVA
- Fundación Cellex
- “la Caixa” Foundation
- Francis Crick Institute
- Ministerio de Ciencia, Innovación y Universidades
- Department of Industry, Tourism and Trade
- Cancer Research UK
- Bundesministerium für Bildung und Forschung
- Euskal Herriko Unibertsitatea
- Banco Bilbao Vizcaya Argentaria
- Fundação Champalimaud
- Stand Up To Cancer
- Instituto de Salud Carlos III
- Agencia Estatal de Investigación
- Berrikuntza + Ikerketa + Osasuna Eusko Fundazioa