Abstract

Most breast cancer (BC) fatalities are due to a metastasis and not the primary tumor. Breast cancer brain metastasis (BCBM) confers an especially grave prognosis, and patients often experience rapid declines in self-sufficiency and neurocognitive function with death typically ensuing in less than a year. There are limited effective treatment options for these patients and improved models of breast cancer brain metastasis (BCBM) are needed to elucidate tumor pathobiology and discover and test effective therapeutics. Brain organoids are self-organizing 3D structures that can be generated from pluripotent stem cells (PSC) and contain many of the morphological, functional and molecular features of the developing human brain. We are developing and characterizing a 3D, cell culture, BCBM model consisting of forebrain organoids invaded with BC cells. We will show that BC cells invade into the interior of forebrain organoids and the neural TME has a large impact on BC cell growth. Outgrowth of micrometastasis to macrometastasis is the rate limiting step of the metastatic cascade. We hypothesize that our BCBM model can be used to study molecular mechanisms driving this process and lead to therapeutics that block development of macrometastasis.

Immunotherapy has revolutionized treatment for some tumors and, although not as successful in GBM, a thorough understanding of immune evading mechanisms may lead to more effective treatments. We have developed a method to probe the immune environment using RNAseq of bulk tumor tissue. We show there are 7 immune subtypes with distinct clinical outcomes, molecular features, infiltration of immune cell types and expression of genes involved in immunosuppression mechanisms. Our in silico analysis suggests that one subtype suppresses the immune system by downregulating machinery necessary for Tcells and Natural Killer Cells to recognize and attack the tumor and identifies therapeutics that may block this immunosuppression. Our results indicate that this approach can identify physiologically relevant immune subtypes, investigate tumor immunosuppression mechanisms and predict which immunotherapy will be effective for a GBM patient.

Speaker Bio

Dr. Joy is a Research Associate Professor in the Center for Computational Systems Biology at Prairie View A & M University. She received her Ph.D. in Chemistry from Arizona State University. During her postdoctoral fellowship at Barrow Neurological Institute she studied the molecular features and pathobiology of brain tumors and continued these studies at as Associate Scientist at Barrow Neurological Institute and the Translational Genomics Research Institute. She joined the Center for Computational Systems Biology at Prairie View at the end of 2018.

The major focus of Dr. Joy’s research includes (1) Identify glioblastoma subtypes and their molecular drivers then develop biomarkers to guide personalized treatment, (2) Understand the role of the three forms of a tumor driving protein called AKT in glioblastoma and (3) Leverage public proteomic and genomic databases to investigate the topology of tumor promoting pathways in Glioblastoma tumors.