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<p>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.</p>

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Fibroblastic aspartoacylase suppresses TGFβ-mediated responses and cancer progression

  • 期刊论文

  • 出版模式：

    开放获取

  • 发表日期：

    2026年6月16日

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  • Ianire Astobiza,
  • Catalina Capó-Serra,
  • Cristina Viera,
  • Javier Rodríguez,
  • Patricia Carnicero,
  • Miguel Juliá,
  • Ainara Martinez,
  • Carmen Pérez-López,
  • María Subijana,
  • Carolina Ortiz-Sanz,
  • Saioa Garcia-Longarte,
  • Isabel Mendizabal,
  • Emily J. Kay,
  • Carla Riera-Domingo,
  • Silvia Rivis,
  • Onintza Carlevaris,
  • Leire Egia-Mendikute,
  • Sara Cascais,
  • Natalia Martín-Martín,
  • Sonia Fernandez-Ruiz,
  • Veronica Torrano,
  • Jana R. Crespo,
  • Mikel Pujana-Vaquerizo,
  • Elisa Espinet,
  • Andreas Trumpp,
  • Noemi Eiro,
  • Francisco J. Vizoso,
  • Ana Vivancos,
  • Joan Seoane,
  • David Gonzalo,
  • Sofia Rey,
  • Aida Santos-Martin,
  • Aitziber Ugalde-Olano,
  • Claudia Manini,
  • Jose I. Lopez,
  • Diana Cabrera,
  • Sebastian M. Van Liempd,
  • Juan M. Falcon-Perez,
  • Roger R. Gomis,
  • Asís Palazon,
  • Christian Frezza,
  • Mireia Castillo-Martin,
  • Sara Zanivan,
  • Massimiliano Mazzone,
  • Miguel Unda,
  • Ana Loizaga-Iriarte,
  • Arkaitz Carracedo,
  • Fernando Calvo

摘要

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.