Abstract
Genetic aberrations driving pro-oncogenic and pro-metastatic activity remain an elusive target in the quest of precision oncology. To identify such drivers, we use an animal model of KRAS-mutant lung adenocarcinoma to perform an in vivo functional screen of 217 genetic aberrations selected from lung cancer genomics datasets. We identify 28 genes whose expression promoted tumor metastasis to the lung in mice. We employ two tools for examining the KRAS-dependence of genes identified from our screen: 1) a human lung cell model containing a regulatable mutant KRAS allele and 2) a lentiviral system permitting co-expression of DNA-barcoded cDNAs with Cre recombinase to activate a mutant KRAS allele in the lungs of mice. Mechanistic evaluation of one gene, GATAD2B, illuminates its role as a dual activity gene, promoting both pro-tumorigenic and pro-metastatic activities in KRAS-mutant lung cancer through interaction with c-MYC and hyperactivation of the c-MYC pathway.
Highlights
Genetic aberrations driving pro-oncogenic and pro-metastatic activity remain an elusive target in the quest of precision oncology
We first leveraged published transcriptome comparisons of spontaneous lung adenocarcinomas and metastases isolated from KrasLA1/+, p53R172HΔG/+ mice[17] in order to select 615 genes (p < 0.01, paired t-test) up-regulated in KrasLA1/+, p53R172HΔG/+ metastases compared to primary tumors
Despite major improvements made with early detection, and increased knowledge and identification of actionable tumor biomarkers, KRASdriven lung adenocarcinoma still represents a commonly diagnosed form of Non-small cell lung cancer (NSCLC) for which there are no targeted agents
Summary
Genetic aberrations driving pro-oncogenic and pro-metastatic activity remain an elusive target in the quest of precision oncology To identify such drivers, we use an animal model of KRAS-mutant lung adenocarcinoma to perform an in vivo functional screen of 217 genetic aberrations selected from lung cancer genomics datasets. In vivo functional screening of a gene library informed by oncogenomics-guided integration of mutant KRAS-specific mouse and human gene signatures reveal several genes whose expression promote tumor growth and/or metastasis, as outlined here and in the companion paper Among those genes, functional characterization of GATAD2B illuminates its role as a potent driver of tumor growth and metastasis in KRASdriven lung cancers. We further show here that high GATAD2B expression correlates with worsened outcomes in lung cancer patients and cooperates with KRAS to promote gain-of-function pro-oncogenic and pro-metastatic transcriptional programs including MYC to mediate cell invasion in vitro and tumor progression in vivo
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