Investigation of Smad2/3-YAP complex as a chemoresistant factor in TP53

• Grant number: 17/06511-8
• Support Opportunities: Scholarships in Brazil - Post-Doctoral
• Start date: September 01, 2017
• End date: May 31, 2020
• Field of knowledge: Health Sciences - Medicine - Maternal and Child Health
• Principal Investigator: Luiz Gonzaga Tone
• Grantee: Gustavo Alencastro Veiga Cruzeiro
• Host Institution: Faculdade de Medicina de Ribeirão Preto (FMRP). Universidade de São Paulo (USP). Ribeirão Preto , SP, Brazil
• Associated research grant: 14/20341-0 - Interactions between emerging therapeutic targets and developmental pathways associated with tumorigenesis: emphasis on pediatric malignancies, AP.TEM
• Associated scholarship(s): 18/20635-4 - Novel strategies and therapeutic targets in medulloblastoma exploring tumor microenviroment trough in vivo models of subgroup SHH and Group 3, BE.EP.PD

Abstract

Medulloblastoma is the most common malignant brain tumor in childhood and it is the main cause of morbidity and mortality in pediatric oncolology. Recent studies revelead 4 molecular subgroups of Medulloblastomas based on the transcriptional, mutational and cytogenetic profiles, these subgroups are: WNT, SHH, Group 3 and Group 4. The SHH molecular subgrupous which bears mutation in TP53 gene shows primary resistance to SMO inhibitor (Vismodegib) and poor prognosis,however, little is known about the molecular mechanism that underlie this agressive phenotype. The molecular pathways TGF-B and Hippo are aberrantly activated in various types of tumors and can perform cross-talks with other pathways causing resistance to chemotherapy and low survival rate. The Smad2/3-YAP complex was recently described and it is considered a key effector and molecular node bewtween TGF-B and Hippo pathway. It can promotes amplification of many transcriptional factors like GLI-2, a key protein of Sonic Hedgehog pathway and it is envolved in primary resistance of TP53 mutant SHH tumor to Vismodegib. This projects aims to develop a double Knockout model of Smad2/3 and YAP using CRISPR/Cas9 technology in MB cell lines TP53 mutant and Wild type. After assessing GLI2 expressions the cells will be treated with Vismodegib. After, apoptosis, proliferation and invasion will be measured. The second phase is to perform the orthotopic injection of these KO Cell lines in mice and treatment with the same inhibitor to assess loss of resistance and survival. We expect to elucidate the mechanism of chemoresistance indentified in MB SHH TP53 mutant tumors and provide informations that will be used for enhancement of disease treatment and prognosis.

Scientific publications

(References retrieved automatically from Web of Science and SciELO through information on FAPESP grants and their corresponding numbers as mentioned in the publications by the authors)

MAGALHAES, TACIANI DE ALMEIDA; DE SOUSA, GRAZIELLA RIBEIRO; CRUZEIRO, GUSTAVO ALENCASTRO VEIGA; TONE, LUIZ GONZAGA; VALERA, ELVIS TERCI; BORGES, KLEITON SILVA. The therapeutic potential of Aurora kinases targeting in glioblastoma: from preclinical research to translational oncology. JOURNAL OF MOLECULAR MEDICINE-JMM, v. 98, n. 4, MAR 2020. (17/06511-8, 16/19820-6, 18/23372-4)

ALENCASTRO VEIGA CRUZEIRO, GUSTAVO; DE ALMEIDA MAGALHAES, TACIANI; RIBEIRO DE SOUSA, GRAZIELLA; BONFIM SILVA, RICARDO; ALBERTO OLIVEIRA DE BIAGI JUNIOR, CARLOS; FERREIRA DAS CHAGAS, PABLO; GOMES DE PAULA QUEIROZ, ROSANE; ALBERTO SCRIDELI, CARLOS; GONZAGA TONE, LUIZ; TERCI VALERA, ELVIS. YAP1 Is a Potential Predictive Molecular Biomarker for Response to SMO Inhibitor in Medulloblastoma Cells. CANCERS, v. 13, n. 24, DEC 2021. (14/20341-0, 17/06511-8, 18/20635-4)