Negative Regulation of Cell Adhesion as a Driver of Brain Metastasis in NSCLC Patients with EGFR Amplification

Brain metastases are strongly associated with a poor prognosis. Experimental animal models have provided valuable insights into the complex biology underlying brain metastasis, and translating these findings could pave the way for innovative management strategies for patients with brain metastases. Between May 2019 and June 2023, twenty-four lung cancer patients and thirty patients with brain metastases from lung cancer were enrolled at Guangdong Sanjiu Brain Hospital. Next-generation targeted panel sequencing (NGS) was performed on lung cancer tissue and surgical specimens from brain tumors for each patient. Brain metastasis mouse models were established through intracardiac injections, and the brain metastasis rate was analyzed. Our results showed that the rate of EGFR amplification was significantly higher in patients with brain metastases compared to lung cancer patients (40% vs. 12%). EGFR-overexpressing PC9 cell lines demonstrated significantly enhanced proliferation and infiltration abilities compared to their parental PC9 counterparts, as evidenced by CCK-8, wound healing, and transwell assays. Moreover, we observed a much higher brain metastasis rate in mice injected with EGFR-overexpressing PC9 cells compared to those injected with parental PC9 cells. RNA sequencing and Gene Ontology (GO) analysis revealed that differentially expressed genes were primarily associated with the "negative regulation of cell adhesion" in biological processes (BP) and "collagen-containing extracellular matrix" in cellular components (CC). This study identifies the negative regulation of cell adhesion as a key driver of brain metastasis in NSCLC patients with EGFR amplification.