In vitro characterization of molecular and functional differences between medulloblastoma subgroups

• Grant number: 14/19976-0
• Support Opportunities: Scholarships abroad - Research Internship - Doctorate
• Start date: April 10, 2015
• End date: April 09, 2016
• Field of knowledge: Health Sciences - Medicine - Maternal and Child Health
• Principal Investigator: Luiz Gonzaga Tone
• Grantee: Gustavo Alencastro Veiga Cruzeiro
• Supervisor: Martin Baumgartner
• Host Institution: Faculdade de Medicina de Ribeirão Preto (FMRP). Universidade de São Paulo (USP). Ribeirão Preto , SP, Brazil
• Institution abroad: University of Zurich (UZH), Switzerland
• Associated to the scholarship: 13/12006-3 - Investigation of new therapeutic targets for medulloblastomas classified according to the molecular subgroups., BP.DR

Abstract

Medulloblastoma (MB) cell dissemination is at the origin of the leptomeningeal metastatic disease, which is a common and severe complication of this malignant, pediatric brain tumor. The molecular mechanisms that mediate MB cell dissemination are largely unknown and no targeted therapy exists to specifically block dissemination. Like many human tumors, MB disease is complex and consists of different tumor entities, each with characteristic genetic and molecular signatures. A consensus was reached in the MB research community to use genetic signatures to assign one of four different subgroup associations (Wnt, Shh, Gr3 and Gr4) to each individual tumor. However, little is still know about functional difference at the mechanistic level that ultimately determine differential behaviors and drug sensitivities of cells of the individual tumors. The identification of the molecular mechanisms that underlie functional differences and of the sub-group-specific driver mechanisms would greatly accelerate the identification of potential drug targets and ultimately provide patients with improved therapies more rapidly. To identify shared and sub-group-specific molecular mechanisms driving MB dissemination, we propose to characterize morphological and molecular characteristics of disseminating medulloblatoma cells derived of tumors with different subgroups. We will use patient material when available as well as laboratory established and patient-derived cell lines. Using quantitative polymerase chain reaction and/or western blotting, we will fist determine expression profiles of a rational selection of potential oncogenic driver genes in clinical isolates and cell lines and compare their expressions to larger collections of publicly available MB clinical datasets. We will then use 3D spheroid cell culture to determine growth and dissemination behavior of laboratory cell lines and orthotopically propagated human MB cell lines with defined subgroup associations. We will test whether subgroup-specific sensitivities to growth factors exist and whether selected targeting of kinases with small molecule drugs impacts differentially on growth and dissemination of cells derived of tumors of different subgroups. As the outcome of this research we expect an improved understanding of general and subgroup-specific pathways that may drive MB pathogenesis and improved insights in expression and function of molecules of potential therapeutic or diagnostic significance. (AU)

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)

VEIGA CRUZEIRO, GUSTAVO ALENCASTRO; SALOMAO, KARINA BEZERRA; OLIVEIRA DE BIAGI, JR., CARLOS ALBERTO; BAUMGARTNER, MARTIN; STURM, DOMINIK; PEIXOTO LIRA, REGIA CAROLINE; MAGALHAES, TACIANI DE ALMEIDA; MILAN, MIRELLA BARONI; SILVEIRA, VANESSA DA SILVA; SAGGIORO, FABIANO PINTO; et al. A simplified approach using Taqman low-density array for medulloblastoma subgrouping. ACTA NEUROPATHOLOGICA COMMUNICATIONS, v. 7, MAR 4 2019. (13/12006-3, 14/20341-0, 14/19976-0, 04/12133-6, 13/02162-8)