BMET-31DEVELOPMENT AND APPLICATION OF A NOVEL MODEL OF HUMAN LUNG-TO-BRAIN METASTASIS TO IDENTIFY UNIQUE METASTATIC GENE SIGNATURES

Abstract

Brain Metastases (BM) are the most common type of cerebral tumor in adult, occurring at a rate 10 times greater than that of primary brain cancers. The inherent abilities of a primary tumor cell capable of initiating a BM resembles that of a cancer stem cell (CSCs). Previous work conducted in our lab identified a population of CSCs within lung-derived brain metastases. We hypothesize that a subgroup of CSCs, termed brain metastasis-initiating cells (BMICs), are responsible for the initiation of BM and are identifiable by an exclusive subset of genes that regulate self-renewal and metastasis. Despite the prevalence and lethality of BM, there is no clinically relevant model that fully reflects metastasis in patients. We recently generated a novel human-mouse xenotransplantation model of BM that allows for interrogation of each phase of the metastatic process from lung to brain, through injection of human patient-derived GFP-expressing BMICs into immunocompromised mice via three routes: 1) intracranial (IC), 2) intrathoracic (IT) and 3) intravascular/intracardiac (IV). GFP+ cells were harvested from the lungs and/or brains from each injection route, and RNA was submitted for microarray analysis to identify a unique metastatic and tissue-specific gene signature. In order to identify genes involved in self-renewal and tumor initiation, we also performed RNA interference screens in vitro and in vivo on BMIC lines against 150 genes implicated in BM formation. Further in vitro validation of select hit genes identified SPOCK1 and TWIST2 as essential regulators of cell proliferation, sphere formation, and migration. Future work will validate the role of these genes in our established in vivo metastasis models. We also aim to examine their expression in primary lung FFPE samples to determine if they are predictive biomarkers of lung-to-brain metastasis in prospective cohorts of newly diagnosed lung cancer patients, and to determine their potential as therapeutic targets.