Research on causal relationship between cancer metastasis premetastatic niche and cellular capacity via histone methylation

Cancer cells are known to have deregulated energy metabolism featuring aerobic glycolysis and preferred utilization of glutamine and glycine. Such cell-autonomous rewiring of intermediary metabolism supports biosynthesis of structural macromolecules and enables rapid cell mass expansion. Deranged mitochondrial metabolism of cancer cells plays permissive role in distant metastasis. It is interesting that pre-metastatic niche (the receiving microenvironment for metastatic cancer cells) usually resides in peri-venular environment with low oxygen tension and less active mitochondrial-dependent respiration. Meanwhile, tissues with uniformly rigorous metabolism such as myocardium and skeletal muscle effectively resist settlement of metastatic colonies. Furthermore, epigenetic regulation appears to be an attractive switch mode for site-specific activation of cancer-receiving phenotype. Based on the seed and soil theory of cancer metastasis, we hypothesize that “epigenetic switch of mitochondrial metabolism in the pre-metastatic niche regulates metastasis focus formation”. We propose three specific aims to test this hypothesis. In Aim 1, we will identify epigenetic regulator(s) of mitochondrial metabolism among histone demethylases whose enzymatic activities can be regulated by post-translational modification. In Aim 2, we will test in vitro if epigenetically altered mitochondrial metabolism in niche component cells drive cancer cell extravasation across an endothelial cell monolayer and support colony formation. Lastly, in the Aim 3 an in vivo approach will be taken to confirm the observations made in the Aim 2. We will bioprint artificial premetastatic niche with bone marrow stromal cells/embryonic fibroblasts from mice conditionally deficient of the histone demethylase identified in the Aim 1. These organoids will be transplanted in an animal model of metastatic breast cancer (the 4T1 orthograft model) and test for their ability to harbour metastatic colonies. Together, the expected products from this research grant will include a platform to study cell biology of pre-metastatic niche, and laboratory evidences for the existence of bioenergetic barrier in target organ microenvironment to curb cancer metastasis. This will expand current knowledge of metabolic regulation of cancer metastasis at the systems level and may lead to novel therapeutic approach for extending cancer survivorship.