RAS-PI3K signalling regulates myCAF phenotype acquisition to modulate tumour progression
Marta Alcón
Centro de Investigación del Cáncer (CSIC-Universidad de Salamanca)
The tumour microenvironment critically shapes cancer progression and therapeutic response. Among its components, cancer-associated fibroblasts (CAFs) actively promote tumour growth, extracellular matrix (ECM) remodelling, invasion, and immune modulation. However, the signalling mechanisms that regulate CAF activation and ECM dynamics remain incompletely understood.
In this seminar, I will present recent findings identifying the RAS–PI3Kα signalling axis as a central regulator of the acquisition of the myofibroblastic (myoCAF) and tumour- promoting CAF phenotypes. Disruption of RAS–PI3K signalling impairs cytoskeletal organisation, reduces nuclear localisation of YAP, and downregulates classical CAF markers such as α-SMA, vimentin, and tenascin C. Using co-culture and decellularized ECM models, we demonstrate that matrices derived from RAS–PI3K-deficient fibroblasts hinder tumour cell proliferation, migration, and epithelial-to-mesenchymal transition. Proteomic analyses further reveal downregulated ECM glycoproteins associated with improved survival in lung cancer patients. In KRAS-driven lung cancer models, fibroblast-specific abrogation of RAS–PI3K signalling leads to reduced tumour burden and altered immune cell infiltration.
Collectively, these findings uncover a stroma-intrinsic mechanism by which RAS–PI3K signalling sustains CAF activation through YAP, thereby supporting tumour progression.
Targeting this regulatory axis may offer novel therapeutic opportunities to remodel the tumour microenvironment and enhance treatment efficacy in KRAS-mutant lung cancer.