Identification of BAIAP2 and CDC42 as potential therapeutic targets in SHH medulloblastoma

PROJECT SUMMARY/ABSTRACT The most common malignant pediatric brain tumor is medulloblastoma. Despite advancements in treatment, medulloblastoma survivors have significant long-term medical side effects and increased all-cause mortality. That is why novel, more effective, and safe treatments are direly necessary. One treatment challenge is that

medulloblastoma tumors can disseminate via the bloodstream and cerebrospinal fluid leading to worse prognosis. The underlying mechanisms that promote metastasis in medulloblastoma are not clearly understood. One method we used to identify potential key regulators in the pathogenesis of medulloblastoma

is by analyzing microarray and single-cell RNA sequencing data. We mined publicly-available datasets along with our data from genetically engineered models of the SHH subgroup of medulloblastoma to identify differentially expressed genes compared to non-tumor brain cells. We identified BAIAP2 and CDC42 to be

differentially expressed and have higher expression in medulloblastoma compared to other brain cancers. BAIAP2 and CDC42 are known to be implicated in migration, invasion, and actin polymerization. Several studies demonstrate an interaction between BAIAP2 and CDC42 in multiple cell types. However, BAIAP2 and

CDC42 have yet to be studied in medulloblastoma. We hypothesize that CDC42 interacts with BAIAP2 in medulloblastoma cells to facilitate tumor pathogenesis. For the first aim of my proposal, I will assess whether the BAIAP2-CDC42 interaction promotes invasion and migration in medulloblastoma. To further investigate

this, we conducted siRNA-mediated gene knockdown of BAIAP2 and CDC42 in ONS-76 cells, representative of the SHH subgroup of medulloblastoma. Our preliminary analysis shows that BAIAP2 and CDC42 are highly expressed in medulloblastoma, and knockdown of BAIAP2 modulates CDC42 expression. Further, we determined that cell proliferation and migration were reduced upon BAIAP2 and CDC42 knockdown. Our

findings suggest that BAIAP2 and CDC42 have a role in the migration and proliferation of medulloblastoma ONS-76 cells. The second aim of my proposal is to determine whether the BAIAP2-CDC42 interaction is necessary for MB invasion and tumor growth in spheroid culture and in vivo. We will utilize siRNA-mediated

knockdown to determine the effect of BAIAP2 and CDC42 knockdown in multiple models of medulloblastoma including cerebellar organoids and medulloblastoma spheroids. We are currently in the process of validating a compound screening to target BAIAP2 and CDC42. These compounds will be tested in medulloblastoma in

vitro, in vivo, and ex vivo to determine potential candidates. There are non known compounds that target the BAIAP2-CDC42 interaction, let alone BAIAP2 alone. Altogether, our preliminary findings indicate BAIAP2 and CDC42 as possible targets for future studies in medulloblastoma. Our proposal will be the first to define

and characterize the potential oncogenic roles of BAIAP2 and CDC42 in medulloblastoma.