#IDIBELLfellows: Lara Ruiz & Pilar Salamanca

Fatty acid signaling drives lymphangioleiomyomatosis
Lara Ruiz Auladell – Molecular signaling in cancer group
Introduction: While low-fat diets are commonly recommended to control chylous effusions in lymphangioleiomyomatosis (LAM) patients, the mechanistic effects of dietary fats on disease progression remain poorly understood. Combining biomarker discovery with in vitro and in vivo studies, we identify the oleic acid–PPARβ/δ–ANGPTL4 signaling axis as a critical mediator of LAM neoplastic and metastatic features. Methods: We performed integrative biomarker discovery using transcriptomic datasets, plasma biomarker measurements in LAM patients, and functional analyses in multiple LAM cell models. The regulation of ANGPTL4 by PPARβ/δ and dietary fatty acids was investigated via genetic and pharmacological approaches. A syngeneic mouse model of LAM lung metastasis was employed to assess the effects of low- and high-fat dietary interventions in vivo. Results: Plasma levels of the lung metastasis-associated factor ANGPTL4 were elevated in LAM patients and overexpressed in LAM cells and lung lesions. Functional assays demonstrated that ANGPTL4 promotes LAM cell proliferation, clonogenicity, migration, and paracrine angiogenesis. ANGPTL4 expression was transcriptionally regulated by PPARβ/δ. Among major dietary fatty acids, oleic acid selectively induced ANGPTL4 expression and enhanced LAM cell clonogenic growth, mediated by increased fatty acid oxidation and reduced oxidative stress vulnerability. In vivo, high- fat diet feeding significantly increased lung metastatic burden in mice, accompanied by elevated plasma and intratumoral ANGPTL4 levels. Conclusions: Our findings identify the oleic acid–PPARβ/δ–ANGPTL4 axis as a pleiotropic driver of LAM tumorigenesis, mechanistically linking dietary fat composition to disease progression. These results suggest that dietary interventions targeting fatty acid intake may offer a novel adjunctive strategy for LAM management.

Chromatin remodeling and the tumor immune microenvironment in mCRPC
Pilar Salamanca Jiménez – Resistance and progression mechanisms in prostate cancer group
Despite advances in prostate cancer (PCa) diagnosis and treatment, many patients progress to metastatic castration-resistant prostate cancer (mCRPC), for which therapeutic options remain limited. Immunotherapy has emerged as a promising approach, yet clinical trials in mCRPC have shown limited success, partly due to a poor understanding of the interaction between cancer cells and the tumor microenvironment. We previously demonstrated that the epigenetic regulator NSD2 promotes mCRPC progression and that its inhibition increases survival in PCa models. GSK126 is an inhibitor of EZH2, which is associated with advanced disease and poor prognosis in PCa, highlighting its potential as a therapeutic target. In this project, we investigate NSD2 as a predictive marker of response to EZH2 inhibition and assess whether GSK126 can be integrated into combinatorial immunotherapy strategies to overcome immune resistance in mCRPC. We focused on the tumor immune microenvironment (TIME) in PCa using genetically engineered mouse models (GEMMs) to assess its impact on lineage plasticity and TIME remodeling.