Targeting c-fos to suppresses metastasis in BRMS1v2 germline mutant lung adenocarcinoma patient derived cells

ABSTRACT: Approximately 50% of patients with early-stage, surgically resected lung cancer will develop distant metastasis. There remains an unmet need to identify patients likely to develop recurrence and to design innovative therapies to decrease this risk. Two primary isoforms of BRMS1, v1 and v2 are present in humans. Using next generation sequencing of BRMS1 on matched human noncancerous lung tissue and NSCLC specimens we identified single-nucleotide polymorphism rs1052566 that results in an A273V mutation of BRMS1v2.  This SNP is  homozygous (BRMS1v2A273V/A273V) in 8% of the population and correlates with aggressive biology in lung adenocarcinoma (LUAD). Mechanistically we show that BRMS1v2 A273V abolishes the metastasis suppressor function of BRMS1v2 and promotes robust cell invasion and metastases by activation of c-fos-mediated gene-specific transcriptional regulation. Specifically, BRMS1v2 A273V increases cell invasion in vitro and increased metastases in both tail-vein injection xenografts and LUAD patient-derived organoid (PDO) intracardiac injection metastasis in vivo models. Moreover, we show that BRMS1v2 A273V fails to interact with nuclear Src, thereby activating intratumoral c-fos in vitro. Higher c-fos results in upregulation of CEACAM6, which drives metastases in vitro and in vivo. Using both xenograft and PDO metastasis models, we repurposed T5224, a c-fos pharmacologic inhibitor investigated in clinical trials for arthritis, and observed suppression of metastases in BRMS1v2A273V/A273V LUAD in mice. Collectively, we elucidate the mechanism of BRMS1v2A273V/A273V-induced metastases and offer a putative therapeutic strategy for patients with LUAD with this germline alteration. 

ORGANISM(S): Homo sapiens

PROVIDER: GSE211809 | GEO | 2022/12/01

REPOSITORIES: GEO