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The role of the Hedgehog signaling pathway in ependymoma

Grant number: 18/18842-1
Support type:Scholarships abroad - Research Internship - Doctorate
Effective date (Start): February 01, 2019
Effective date (End): January 31, 2020
Field of knowledge:Health Sciences - Medicine
Principal Investigator:Luiz Gonzaga Tone
Grantee:Taciani de Almeida Magalhães
Supervisor abroad: Adrian Salic
Home Institution: Faculdade de Medicina de Ribeirão Preto (FMRP). Universidade de São Paulo (USP). Ribeirão Preto , SP, Brazil
Local de pesquisa : Harvard University, Boston, United States  
Associated to the scholarship:16/19820-6 - Investigation of new therapeutic targets from transcriptional networks of genes of the mitotic spindle associated with embryonic developmental pathways in the ependymoma: focus on molecular subgroups of worst outcome, BP.DR

Abstract

Ependymoma (EPN) is the third most frequent brain tumor in children. This tumor is a heterogeneous disease, which can be classified in nine molecular subgroups. The subgroups ST-EPN-YAP1, ST-EPN-RELA and FP-EPN-A are more frequent in children. ST-EPN-RELA and FP-EPN-A subgroups are associated with poor prognosis and resistance to therapy. Our project is focused on understanding specifically the ST-EPN-RELA subgroup, which accounts for 70% of all childhood supratentorial tumors, and currently has the worst prognosis among them. Due to the low efficacy of the chemotherapy the treatment options for this subgroup are limited. Interestingly, we discovered that the Hedgehog pathway is activated in some of the EPN subgroups with the worst prognosis. Briefly, we found that the Hedgehog ligands DHH and IHH are aberrantly expressed in ST-EPN-RELA (and BXD-1425 cell line classified as RELA) and in FP-EPN-A, respectively. We also detected high expression of the positive Hedgehog regulators, SMO and GLI1, and reduced expression of the negative regulators, PTCH1 and SUFU, in these subgroups. These findings suggested that the Hedgehog pathway is activated in EPN, possibly by different ligands, depending on the tumor subgroup. Since primary cilia are essential for Hedgehog signaling, we found a robust ciliation in EPN cell line BXD-1425, derived from a ST-EPN-RELA tumor. Treatment with LDE225, a small molecule inhibitor of the Hedgehog pathway that functions as Smoothened antagonist, had strong anti-proliferative and pro-apoptotic effects on BXD-1425 cells and inhibited transcription of GLI1, a direct target of the Hedgehog pathway, as well as led to a marked decrease in expression of Hedgehog components DHH, SMO, PTCH1 and SUFU. Taken together, our findings support the novel idea that the Hedgehog pathway plays an important role in EPN subgroups with a poor clinical prognosis. However, further studies are necessary to elucidate the mechanisms of Hedgehog pathway activation involved in EPN, both in cell culture and in in vivo models. The identification of these molecular mechanisms will greatly accelerate the identification of potential drug targets, and will ultimately provide pediatric patients with novel and improved therapies in ST-EPN-RELA. The team at Harvard Medical School has the appropriate expertise and collaborators in place to rapidly translate these findings in an efficient manner to improve treatment outcome in this devastating pediatric brain cancer.