Establishment of transgenic models to investigate the participation of astrocytes in the progression of Sonic Hedgehog medulloblastoma

• Grant number: 22/15067-2
• Support Opportunities: Scholarships in Brazil - Scientific Initiation
• Start date: June 01, 2023
• End date: May 31, 2024
• Field of knowledge: Health Sciences - Medicine - Maternal and Child Health
• Principal Investigator: Silvia Aparecida Teixeira
• Grantee: João Vitor Borduqui
• Host Institution: Hospital do Câncer de Barretos. Fundação Pio XII (FP). Barretos , SP, Brazil

Abstract

Medulloblastoma (MB), a malignant tumor originating in the cerebellum, represents 20% of tumors of the Central Nervous System in infants, children, and young adults. Specifically, for medulloblastomas associated with the Hedgehog signaling pathway (SHH), research has shown that host cells in the tumor microenvironment influence the biological behavior of tumor cells, contributing to the progression of this subtype. Recent data reinforce the claim that the microenvironment should be considered for a more refined molecular diagnosis risk stratification when planning personalized clinical approaches. Despite recent studies pointing to the participation of astrocytes in the progression of the MB-SHH subgroup, the mechanisms by which these cells affect tumor survival and growth still need to be fully understood. Thus, in mice that develop MB-SHH, this proposal will investigate the participation of astrocytes in tumor evolution and progression. For this, we will use transgenic mice and the Cre-loxP system to promote the development of MB from the deletion of PTCH1 in precursors of cerebellar granular neurons (Math1). In double-positive transgenic mice (Math1-Cre/PTCH1-loxP), it will be possible to characterize, by histopathological detection, these astrocytes from the tumor microenvironment, the hyperplastic cerebellar lesions, the progression, and tumor establishment. The experiments with transgenic mouse models will provide critical insight to identify key targets for potential astrocyte-targeted therapies and will be used as appropriate preclinical models for evaluating these therapies.