TMOD-37. CHARACTERIZATION OF A UNIQUE BMIC POPULATION IN HUMAN BRAIN METASTASES

Brain Metastases (BM) are the most common neoplasm to affect the adult central nervous system, occurring at a rate 10 times greater than that of primary brain cancers. Despite the prevalence and severe lethality of BM, the current available in vivo models of metastasis neither fully recapitulate the clinical progression of BM nor allow for proper examination of metastatic cells. Not every cell within a primary tumour possess the ability to survive metastasis, and studies typical investigate large macro-metastases formed by cells that have already exited the metastatic cycle. We hypothesize that within primary tumours exists a subpopulation of CSC-like cells, termed brain metastasis-initiating cells (BMICs), which are responsible for initiating BMs. We have recently generated a novel patient-derived xenotransplantation (PDX) model of BM that allows for interrogation of each phase of the metastatic process from lung to brain, through injection of human patient-derived BMICs into immunocompromised mice. We then expanded our model to incorporate BMs from breast and melanoma primaries. BMICs were harvested from primary sites and corresponding BMs, and RNA submitted for sequencing to identify a metastatic and tissue-specific gene signatures. From our novel PDX model we were able to interrogate micro-metastasis formation, where we found BMICs to possess a unique genomic profile as compared to BMICs isolated from full primary tumors and complete macro-metastases. These BMICs exhibit increased expression of stem cell, epithelial-to-mesenchymal transition, and quiescence genes. Through in silico analysis we generated a preliminary list of therapeutics targeting these unique BMICs. Future work will identify novel therapeutics that block the metastatic process by targeting these unique BMICs, and assess the clinical utility of this novel BMIC signature in predicting BMs of different origins. Ultimately we aim to transform a uniformly fatal systemic disease into a locally controlled and eminently more treatable one.