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Ex Vivo Analysis of Human Brain Tumor Cells in a Microvascular Niche Model

The perivascular niche (PVN) in human brain tumors is an important microenvironment for the maintenance of brain tumor stem-like cells (BTSCs), the development of resistance to chemo or targeted therapies, and the path for tumor cells to invade distant regions in the whole brain, leading to incurable diseases. Current in vitro models such as 2D cell cultures or 3D tumoroids do not contain this niche environment. Mouse models of brain tumors can recapitulate some aspects of the PVN, but have major limitations including high cost, low throughput, and the inability to perform live cell tracking of individual BTSCs. Herein, we propose to develop a tissue-engineered 3D microvascular niche-on-a-chip model that can incorporate primary brain tumor cells from patients in order to bridge this gap between in vitro and in vivo models.

Our pilot study has demonstrated the success in co-culture of patient-derived glioblastoma cells and microvasculature in a microfluidic gel system and observed preferential localization of BTSCs in the PVN. Comparing ex vivo dynamics of individual tumor cells on-chip to single-cell transcriptomes across 10 patients further revealed a correlation between perivascular localization and transcriptional subtypes. In this project, we propose to further examine tumor cell migration and localization using a larger cohort of patient specimens and compare the results to pathological and clinical data, aiming to develop it into an ex vivo functional assay for patient prognosis and subclassification (Aim 1). We will apply scRNA-seq to the same samples to generate correlative data to identify subtypes associated with distinct ex vivo dynamics in the tissue-engineered PVN model, which can help elucidate the molecular mechanisms of PVN in tumor cell fate and invasion (Aim 2). Finally, we will investigate the response of tumor cells in PVN to chemo and targeted therapies administered through the perfusable microvascular network to assess the potential to perform personalized drug test and therapeutic stratification (Aim 3). This project will deliver a novel tissue-engineered microsystem to not only study the biology of PVN in human brain tumor development but also develop new assays for ex vivo drug test of human tumor cells for precision medicine.

Investigators

This project consists of researchers from Yale University.

Rong Fan, Ph.D.
Rong Fan Lab

Rong Fan is Associate Professor of Biomedical Engineering at Yale University. He received a B.S. in Applied Chemistry from University of Science and Technology of China in 1999, a Ph.D. in Chemistry from the University of California at Berkeley in 2006, and completed a postdoctoral training in cancer technology at California Institute of Technology before joining the faculty of Biomedical Engineering at Yale University in 2010.

His research is focused on the development of microchip technologies for single-cell or spatial multi-omics analysis as well as the development of tissue-engineered microsystems to model human diseases for precision medicine. Recently, his laboratory developed microvasculature-on-a-chip model and applied it to the study of tumor-microvessel interaction. He is the recipient of the NCI Howard Temin Pathway to Independence Award, the NSF Early Stage Faculty Career Development (CAREER) Award and the Packard Fellowship for Science and Engineering.

 
headshot of Jiangbing Zhou, Ph.D.
Jiangbing Zhou, Ph.D.
Zhou Research Lab

Jiangbing Zhou is Associate Professor of Neurosurgery and of Biomedical Engineering at Yale University. He received a B.S. in Chemical Engineering from East China University of Science and Technology in 1998, a Ph.D. in Molecular Microbiology and Immunology from Johns Hopkins University in 2008, and did postdoctoral research in Mark Saltzman’s laboratory at Yale University before joining the faculty of Neurosurgery at Yale School of Medicine in 2011.

His research group focuses on developing translational nanomedicine, gene therapy, and stem cell therapy for treatment of neurological disorders through a unique combination of material science, biology, and engineering. In particular, he was among the first group of scientists studying cancer stem cells in solid tumors back to 2002 when he started the doctoral research at Johns Hopkins University. Recently, his laboratory has established >12 patient-derived brain tumor stem cell cultures for the study of brain tumor stem cell differentiation and therapeutic responses.

 
headshot of Anita Huttner, M.D.
Anita Huttner, M.D.
Anita Huttner, M.D. at Yale School of Medicine

Anita Huttner is Associate Professor of Pathology at Yale School of Medicine and Director of Neuropathology. He received a M.D. from University of Erlangen, School of Medicine, Germany, completed residence at Yale School of Medicine, and clinical fellow training at Harvard Medical School. She is the Associate Director for Yale Pathology Tissue Services (YPTS) with access to a wide range of human tissues and provides tissue-based analysis. She is trained and board-certified in Anatomic Pathology, Neuropathology and Molecular Genetic Pathology.

As Clinical Neuropathologist she is experienced with the analysis of human brains with particular focus on CNS neoplasia. Research in her laboratory is focused on disease modeling via induced pluripotent stem cell and organoid technology, particularly of neurodevelopmental disorders and neoplasia.

 
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