Project Summary
Title: Neural Niche in Promoting Brain Metastasis Progression
Metastatic progression at the brain is a multi-step, evolutionary process that is accomplished through a
consistent interplay between disseminated tumor cells and brain microenvironment - "the niche". Despite
significantly improved control of primary tumors, the incidence of brain metastasis is increasing! To reduce
cancer mortality, rationally-designed therapeutics, based on a mechanistic understanding of metastasis in at
the unique brain metastatic niche, are urgently needed for brain metastasis patients. What's the brain
metastatic niche? In the brain microenvironment - the niche - is a myriad of diverse cell types that have been
speculated to contribute to the brain tumor and brain metastasis development, including endothelial cells,
astrocytes, neural stem/progenitor cells (NSC hereafter) and increasingly appreciated brain immune cells.
Despite studies of astrocytes, how do the NSC and its progenies respond to brain metastatic colonization and
regulate brain immune landscape and the metastatic outcome has yet to be systematically investigated. Our
preliminary studies have demonstrated that NSC migrates to colonized tumor cells and NSC is functionally
essential for brain metastasis progression. Intriguingly, ample evidence from in the field of neuroscience
suggests an immune suppressive role of NCS during the brain inflammation. Thus, in this proposal, we
hypothesize that NSC and its progenies' brain metastasis tropism and potentially consequential
immunosuppressive activity could contribute to an immune-suppressive metastatic niche, facilitating brain
metastasis progression. In this proposed study, we will use transgenic mouse models and state-of-the-art
genomics and imaging approach to trace and analyze the role of highly heterogeneous cell types involved in
NSC differentiation and immune suppression and their roles in regulating brain metastatic outgrowth. This
collaborative effort integrating multidisciplinary expertise, including cancer biology, neuroscience,
computational biology, allow us to: 1) examine and trace the NSC differentiation response to brain metastasis
at the phenotypical level; 2) visualize and quantitatively measure the behavior of brain metastatic niche cells
and their transcriptome heterogeneity; 3) examine the mechanism by which neural cells derived from NSC
promotes brain metastasis progression. New in-depth mechanistic insights obtained through basic and pre-
clinical innovative research will pave the way to future brain metastases treatments.