Abstract
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, therapeutic strategies remain limited. Advancements in in vivo modelling of metastasis presents a useful platform to aid in the advance and screening of novel targeting therapeutics, though currently few models exist that properly recapitulate the clinical progression of brain metastasis. Utilizing primary patient samples of BMs, we have characterized a subpopulation of CSC-like cells, termed brain metastasis-initiating cells (BMICs), which are responsible for initiating BMs. Through injections of BMICs isolated from lung BMs into NOD-SCID mice, we have generated a novel patient-derived xeno-transplantation (PDXT) model of BM that allows for interrogation of each phase of the metastatic process from lung to brain. We then expanded our model to incorporate BMICs derived from breast and melanoma BMs. BMICs were harvested from primary sites and corresponding BMs, and RNA submitted for sequencing to identify metastatic and tissue-specific gene signatures. BMICs were found to possess a unique genomic profile as compared to BMICs isolated from full primary tumors and complete macro-metastases, exhibiting dysregulated expression in over 13,000 genes, including those involved in stem cell, epithelial-to-mesenchymal transition, and quiescence properties. In silico analysis was used to generate a list of therapeutics targeting this unique BMIC population. In vitro and in vivo screening has identified a subset of compounds with no previously known efficacy in cancer treatment that inhibits BMIC growth and metastasis. Ultimately, we aim to transform a uniformly fatal systemic disease into a locally controlled and eminently more treatable one.http://ift.tt/2zzhfm6
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