FUS inactivation promotes leptomeningeal metastasis of lung cancer through the up-regulation of CD36.
TL;DR
In patients with NSCLC, in patients with NSCLC, down-regulation of FUS or up-regulation of CD36 or SYP was associated with progression to LM, highlighting CD36 as a promising therapeutic target to limit the progression of LM.
Abstract
The prognosis of non-small cell lung cancer (NSCLC) with leptomeningeal metastasis (LM) is dismal. The regulators of LM progression remain elusive, thus impeding effective clinical intervention. Here, we performed in vivo genome-wide CRISPR-based screens and found that fused in sarcoma (FUS) ablation promoted LM in both PC9 and A549 cells. FUS repressed CD36 expression by directly interacting with and destabilizing PPARA (peroxisome proliferator-activated receptor α) messenger RNA. CD36 augmented fatty acid uptake and oxidative phosphorylation in NSCLC cells. Matrix metallopeptidase 2 (MMP2) was up-regulated through CD36-mediated fatty acid metabolism, which enabled NSCLC cells to disrupt the endothelial barrier. FUS-deficient NSCLC cells increased the expression of neuroendocrine differentiation (NED)-related markers, including SRY-box transcription factor 2 (SOX2), microtubule-associated protein 2 (MAP2), enolase 2 (NSE), and synaptophysin (SYP). They also exhibited neurite-like extensions and expanded in cerebrospinal fluid-supplemented medium in a CD36-dependent manner. Mechanistically, fatty acid uptake increased acetyl-coenzyme A and H3K27ac modifications to promote the expression of NED signature genes and MMP2 in NSCLC cells. Genetic or pharmacological inhibition of CD36 or inhibition of NED-related markers in NSCLC cells hindered LM and prolonged survival in mice. In patients with NSCLC, down-regulation of FUS or up-regulation of CD36 or SYP was associated with progression to LM. Thus, CD36-mediated fatty acid metabolism and NED signature are crucial for progression to LM in NSCLC, highlighting CD36 as a promising therapeutic target to limit the progression of LM.