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.