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Abstract Introduction: Medulloblastoma (MB) is the most common malignant brain cancer in children. Although long-term survival has improved in recent years, only a modest percentage of patients survive high-risk disease. The quality of life for those who survive is substantially reduced due to the high toxicity associated with the radiation and chemotherapy. Therefore, identification of safe and potent therapeutic approaches that can sensitize the therapy response in MB without inducing toxicity will lead to more efficient treatment of MB patients. We recently discovered that targeting HDGFRP3, a protein highly expressed in MB, and can block MB growth and improve the efficacy of radiation therapy. HDGFRP3 is a multifaceted protein that plays important roles in diverse cellular processes. Our investigation sheds light on the functional role of HDGFRP3 in MB, focusing on its involvement in growth, progression, and radioresistance where we report HDGFRP3 as a novel oncogenic driver of these processes. Methods: Human MB cell lines (DAOY, D556, D425, and HDMB03) were purchased from the American Type Culture Collection and cultured in standard medium. MB cancer cells were transfected with siRNA specific to HDGFRP3. These knockdown cells were analyzed for cell viability, migration, invasion, colony formation, stemness, cell cycle, apoptosis assays for functional role assessment. Real-time qPCR and western blotting were performed to validate the downstream targets of HDGFRP3 in MB models. Results: Our findings demonstrate that HDGFRP3 functions as an oncogene in MB, as its overexpression promotes cancer growth, while its depletion results in decreased tumor growth in MB models. Furthermore, we provide evidence that HDGFRP3 knockdown results in decreased migratory potential of MB cells as well as a reduction in stemness. Interestingly, HDGFRP3 depletion improved the efficacy of standard of care radiation in multiple MB models. At present, in vivo studies are validate the oncogenic role of HDGFRP3 in preclinical animal models of MB. Conclusions: In conclusion, our data suggests HDGFRP3 facilitates MB growth, progression, stemness as well as resistance to radiation therapy. Our comprehensive investigation into HDGFRP3's functional role in MB presented here provides valuable insights into its potential as a therapeutic target and opens avenues for further research into novel treatment strategies for the pediatric brain tumors. Citation Format: Saif S. Nirzhor, Prabhakar Pitta Venkata, Shahad Abdulsahib, Panneerdoss Subbarayalu, Santosh Timilsina, Manjeet K. Rao. Unveiling the functional role of HDGFRP3 in pediatric medulloblastoma: Implications for growth, progression, and radioresistance abstract. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts) ; 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84 (6Suppl): Abstract nr 3156.
Nirzhor et al. (Fri,) studied this question.