Elucidating the role of Ybx1 in cerebellar development and medulloblastoma

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Project Summary The cerebellum is part of the mammalian hindbrain which plays important roles in motor control and some cognitive functions, such as language and spatial memory. Although these functions are complex, the continued development after birth and simple structure of the cerebellum make it unique model for understanding postnatal regulation of gene expression, proliferation, and differentiation. Interestingly, the same signaling pathways that play a role in normal cerebellar development are commonly hijacked and altered in cancers, such as medulloblastoma (MB) – the most common malignant pediatric brain tumor. MB is divided into four subgroups, where mutations in these signaling pathways are known to occur in the SHH and WNT subgroups, with very few recurrent alterations in Group3 and 4 tumors. Recent studies, however, have identified a number of overexpressed developmentally regulated genes that are attractive therapeutic targets. Y-box binding protein 1, YBX1, recently identified to control proliferation/differentiation in the developing embryonic brain, is highly expressed in the cerebellum during both proliferative and differentiation phases. Further, YBX1 levels are high in all subgroups of medulloblastoma with the highest expression seen in high-MYC expressing MBs (Group3- G3). Therefore, understanding the functional role of YBX1 in both cerebellar development and in medulloblastoma is highly relevant. Our preliminary studies show that YBX1 is required for proper specification of the cerebellum and that loss of Ybx1 diminishes the growth of G3 MB in vivo. The three aims of this proposal are to: 1) determine the role and function of YBX1 in regulating proliferation/differentiation of cerebellar progenitors, 2) assess the requirement of YBX1 in initiation and progression of medulloblastoma using both human and mouse models, and 3) identify target genes and epigenetic alterations downstream of YBX1. Finally, I will assess if direct antagonism of YBX1 can inhibit tumor growth. This study will uncover new gene regulatory networks of cerebellar development as well as those which regulate MB initiation and progression, leading to the identification of novel targets. The integration of neurodevelopment, stem cell biology, biochemistry, and cancer biology make this an innovative research proposal that will be significant for increasing knowledge about the normal functions of YBX1 as well as solidifying it as a pharmacological target in G3 MB. This proposal builds upon my strong background in epigenetics, stem cell biology, and cancer biology from both my pre- and post- doctoral fellowships. My short-term career goal is to obtain a research faculty position at a leading institution where I will focus on understanding epigenetic mechanisms in normal development and tumorigenesis. With assistance from core facilities here at St. Jude and my future institution as well as collaborations both old and new, this award will allow for further training in CRISPR/Cas9 gene editing and bioinformatics analysis. Completion of this proposal will put me in a perfect position to continue work towards my long-term goal of fulfilling the NCI mission “to advance scientific knowledge and help all people live healthier, longer lives.”