Ex Vivo Modeling of Medulloblastoma using Human iPSC-Derived Cerebellar Organoids
Medulloblastoma (MB) is a deadly form of childhood brain cancer. Recent studies performed on tumor samples obtained from MB patients have discovered that MB is not a single disease, but best characterized as multiple clinically distinct "subgroups". Different MB subgroups are believed to begin in distinct cell types of the developing brain, in a region known as the cerebellum. Current treatments for MB are non-specific and cause significant lifelong side effects that prevent an independent life after cancer. New treatments designed to specifically cure each MB subgroups are needed to improve patient survival and quality of life. The development of new treatments will rely heavily on specialized laboratory models that are currently lacking. We propose to solve this need for specialized models using a modern stem cell technology known as "organoids" to create accurate human disease models for MB. Organoids are miniature versions of human tissues produced from stem cells and maintained outside of a living organism. Organoids are easy to grow and modify, and provide an accurate system for studying human biology. Cerebellar organoids that mimic the developing human cerebellum can be used to simulate various aspects of MB development. This proposal outlines our plan to create multiple MB subgroup models from cerebellar organoids. These new models will be used to investigate how MB begins and survives in an accurate cerebellar system. The development of these models that are specific for each MB subgroup will create new opportunities for drug discoveries that will greatly improve survival of affected children.
Project Goal:
The goal of this project is to use human stem cell-derived cerebellar organoids as a novel system to determine the developmental and molecular basis of MB. Our first aim is to create organoids that accurately reproduce the biology of different MBs, focusing on two poorly understood, clinically aggressive MB subgroups (Groups 3, 4). We will modify stem cells to contain gene mutations present in MB tumors and guide the cells to become cerebellar organoids. Simulating the process of MB development in this system will enable us to study early events of cancer initiation and determine how cells of the normal cerebellum become cancerous. Our second aim is to understand how MB tumor cells communicate with neighboring cerebellar cells to sustain tumor growth and survival. We will combine cerebellar organoids with patient-derived MB tumors, allowing tumors to interact with normal cells in the organoids the way they would in affected children. Monitoring the way MB tumor cells and normal cerebellar cells communicate with each other will allow us to identify the types of signals being transmitted between them. By therapeutically targeting these communication signals in the future, we hope to stop MB tumors from thriving in the cerebellum and cure affected children of their disease. The two types of organoid-based preclinical models described above will advance current MB modeling approaches. This advance will be valuable to scientists and clinicians with interests in cerebellar development and MB biology, ultimately lead to better outcomes for children that urgently need more effective treatment options.
