FUS ablation induces neuroendocrine-differentiation-like phenotypes and promotes leptomeningeal metastases in lung cancer through upregulating CD36 expression

Non-small cell lung cancer (NSCLC) with leptomeningeal metastases (LM) remains a devastating clinical challenge due to its poor prognosis and the lack of well-defined molecular regulators. To address this gap, we performed in vivo genome-wide CRISPR-based screens to identify key drivers of LM progression. We discovered that genetic ablation of FUS (Fused in sarcoma) significantly promotes LM in both PC9 and A549 NSCLC cell lines. Mechanistically, FUS suppresses CD36 expression by directly interacting with and destabilizing PPARA mRNA. Loss of FUS leads to elevated CD36 levels, which in turn enhances fatty acid uptake and oxidative phosphorylation (OXPHOS) in NSCLC cells. This metabolic reprogramming, mediated by CD36, upregulates matrix metalloproteinase 2 (MMP2), enabling tumor cells to breach the endothelial barrier. FUS-deficient NSCLC cells further exhibit neuroendocrine differentiation (NED)-like features, characterized by increased expression of NED markers (e.g., SOX2, MAP2, NSE, SYP), neurite-like extensions, and robust proliferation in cerebrospinal fluid (CSF)-supplemented culture conditions in a CD36-dependent manner. Targeting CD36 with the inhibitor SSO reduces fatty acid uptake, suppresses NED signature gene expression, and inhibits tumor expansion in the CSF environment. Mechanistic analysis shows that fatty acid metabolism increases acetyl-CoA availability and H3K27ac histone modifications to promote the expression of NED signature genes and MMP2 in NSCLC cells. In preclinical models, genetic or pharmacological inhibition of CD36, or inhibition of NED signature in NSCLC cells hindered LM and prolonged survival in mice. In NSCLC patients, FUS downregulation and CD36 or SYP upregulation were associated with aggressive LM progression. Moreover, CD36 expression dynamically fluctuates during disease progression and treatment, highlighting its potential as a biomarker for monitoring therapeutic responses. Collectively, CD36-mediated fatty acid metabolism and NED signature are crucial for LM progression in NSCLC, underscoring CD36 as a potential LM biomarker and a promising therapeutic target for LM treatment.