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Study of the Hippo pathway in medulloblastoma: inhibition of YAP and its relation to cancer stem-cells

Grant number: 15/26419-3
Support type:Scholarships in Brazil - Scientific Initiation
Effective date (Start): April 01, 2016
Effective date (End): December 31, 2017
Field of knowledge:Biological Sciences - Biology
Principal Investigator:Oswaldo Keith Okamoto
Grantee:Lucas Carvalho Price
Home Institution: Instituto de Biociências (IB). Universidade de São Paulo (USP). São Paulo , SP, Brazil

Abstract

The Hippo pathway is a cell signalling pathway which is receiving increasing attention due to works relating its function to organ size control and to the development of different types of cancers. It is composed by a sequence of proteic phosphorilations culminating in the inhibtion of two transcription factors, YAP and TAZ, which are responsible for regulating the expression of genes associated with proliferation and cell survival. A deregulation of this pathway may result in an increased activity of both YAP and TAZ, leading to an organ overgrowth, and if this activity is sustained, to the fomation of tumours. Also, there are evidences of an increased expression of these co-factors both in normal and cancer stem-cells, therefore relating the activity of these proteins to undifferentiated cells. In this project, we aim to study the possible involvement of the YAP protein in the development of medulloblastoma, a malignant embrionary tumour of the central nervous system probably developed from cancer stem-cells. However, its connection to deregulations of the Hippo pathway is not well studied. The first step will be evaluating the effects of Verteporfin - a molecule described to inhibit the activity of YAP in different cell types - in inhibiting YAP in different cell lineages of human medulloblastoma. This effect will be verified by checking the expression of YAP target genes. Next, the effects of verteporfin treatment will be verified on the self-renewing capabilities of medulloblastoma stem-cells through cell viability and proliferation assays, neurosphere generation (cultures enriched for tumour stem-cells) and through the expression of stem-cell markers. This study will allow us to evaluate the consequences of a farmacological inhibition of YAP on the behaviour of medulloblastoma stem-cells.