Role of Primary Cilium Signaling and Dynamics in Medulloblastoma Initiation and Progression
Background: Medulloblastoma is the most common malignant brain tumor affecting children and comprises ~33% of pediatric brain cancers. Medulloblastoma is a tumor originating in the cerebellum and most of these tumors arise from unregulated proliferation of cerebellar granule cells. Current treatment strategies have not changed much over the years and are associated with high morbidity and mortality associated with recurrence. Thus, there is an urgent need for more effective and targeted therapies that reduce toxicity and prevent recurrence. Cerebellar granule cells proliferate after birth in a developmentally regulated process that depends on the signaling molecule sonic hedgehog and the primary cilium, a hair-like dynamic signaling antenna for cells, before migrating and maturing as neurons. However, the role of ciliary signaling in granule cell proliferation and ciliary dynamics during migration/maturation in causing medulloblastoma is not known.
Project Goal: Here, using newly developed mice models and studying patient tumor samples, we propose modeling medulloblastomas, particularly sonic hedgehog subtype, as a disease of aberrant cerebellar granule cell development. We determine mechanisms underlying the balance between cilia-regulated proliferative and maturation signals and study these developmental aspects in the context of tumor initiation and progression. Our fundamental discoveries of key factors in the poorly understood negative regulation of the sonic hedgehog pathway and approaches to study primary cilia dynamics in the context of granule cell cycling and maturation will not only provide much needed unique insights into medulloblastoma initiation and progression, but will also identify key therapeutic targets to treat this devastating pediatric cancer and in preventing recurrence.
Project Update 2021: A recent study identified that mutations in G protein-coupled receptor GPR161 are a predominant factor in genetic predisposition to Sonic hedgehog subtype medulloblastomas affecting children below three years of age. Currently, there is only a single drug Vismodegib that targets the upstream Sonic hedgehog pathway for treating these pediatric tumors. Inhibiting GPR161 and/or cilia might be a way to inhibit progression of these tumors that develop resistance to drugs targeting the upstream Sonic hedgehog pathway. Our work points to an intricate balance between Sonic hedgehog pathway activation and repression during cerebellar development. In recent papers published in Developmental Cell and eLife, we describe other key cellular brakes and relevant signaling zones in Sonic hedgehog pathway regulation. These papers highlight our fundamental discoveries of key factors in the poorly understood negative regulation of the sonic hedgehog pathway. Furthermore, we are undertaking approaches to study primary cilia dynamics in the context of granule cell cycling and maturation (manuscript in preparation). Our published results and ongoing approaches will not only provide much needed unique insights into medulloblastoma initiation and progression but will also identify key therapeutic targets to treat this devastating pediatric cancer and in preventing recurrence. We envision that our ongoing work will allow for the development of new drugs for Vismodegib resistant Sonic hedgehog subtype medulloblastoma.
