Identification of Brain Metastasis Initiating Cells and Regulators of Brain Metastasis from Lung Cancer
A recent study by the Massague group has identified genes that mediated breast cancer metastasis to the brain by using genomic expression analysis to compare in vivo-selected brain metastasis cell lines to the corresponding parental lines. Knockdown of these genes reduced the migration and invasiveness of BM-derived cells in vitro and in vivo. Another group using in vivo selection identified a set of Wnt3a-regulated genes to be predictive of lung metastasis to the brain. While these studies identify genes important in the invasiveness and metastasis of tumour cells to the brain, any involvement in the CSC properties of self-renewal or differentiation has yet to be shown. Furthermore, these gene signatures may be biased by in vivo selection which identifies genes useful in growing in mouse brains; they also lack a primary brain tumour comparison. As such, the true predictive value and involvement in brain metastasis of these genes is uncertain. We will address these limitations by identifying BM genes through genomic comparisons of primary brain and lung tumours to lung-derived BMs, and applying our in vitro and in vivo BTIC models to characterize the importance of these genes in CSC properties and invasion. Prior work conducted in our lab has demonstrated that BMs have a similar sphere-formation capacity as primary brain tumour samples when exposed to neural stem cell (NSC) conditions, where sphere-formation correlates with self-renewal. Known BTIC markers are also expressed in BMs, in percentages similar to those in primary brain tumours however, they were not useful in identifying functionally distinct populations. BMs may also possess a mixed-lineage differentiation capacity. These results are consistent with the presence of a CSC population. In collaboration with Dr. Marco Marra (BC Cancer Agency) we have identified a list of 30 candidate genes as being significantly overexpressed in an enriched stem cell population for BM, primary brain and lung tumours through transcriptome analysis.
Mohini Singh , McMaster University
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