Modeling of embryonic tumor of the central nervous system from neuroprogenitor cel...
| Grant number: | 13/17566-7 |
| Support type: | Scholarships in Brazil - Doctorate (Direct) |
| Effective date (Start): | December 01, 2013 |
| Effective date (End): | July 31, 2016 |
| Field of knowledge: | Biological Sciences - Genetics |
| Principal Investigator: | Oswaldo Keith Okamoto |
| Grantee: | Patrícia Benites Gonçalves da Silva |
| Home Institution: | Instituto de Biociências (IB). Universidade de São Paulo (USP). São Paulo , SP, Brazil |
Abstract Medulloblastoma is a malignant tumor of embryonic origin that frequently occurs in childhood and adolescence. Ranked by the WHO as a grade IV tumor of the central nervous system, medulloblastoma is one of the major causes of morbidity and mortality by cancer in children. A significant proportion of patients does not respond to available treatments which may also induce motor and cognitive disorders. The study of the mechanisms underlying the aggressiveness of medulloblastoma is therefore necessary to better understand the factors determining the clinical outcome of this important pediatric tumor. Several studies have shown that activation of genes typically expressed in stem cells may confer more primitive and aggressive characteristics to tumor cells, often associated with an unfavorable clinical outcome. A recent work published by our group showed that expression of the pluripotency gene OCT4, although sporadic, is correlated with poor survival of patients with medulloblastoma. This finding prompted us to investigate a possible functional role of this gene in medulloblastoma malignancy. The OCT4 gene encodes a transcription factor of the POU family known for its role in the acquisition of a pluripotent cell state. However, recent studies identified distinct OCT4 transcripts, arising from alternative splicing, whose respective encoded isoforms have functions still poorly understood, particularly in the context of cancer. Preliminary results of in vitro experiments indicate that overexpression of OCT4A isoform change cell proliferation, adhesion and anchorage-independent growth in Daoy cells, a established human medulloblastoma cell line, suggesting a possible role of OCT4A in tumor aggressiveness. Thus, the present project proposes to expand the scope of this preliminary study, aiming at obtaining subclonal cell lines from distinct lineages of human medulloblastoma with stable OCT4A overexpression. These subclonal cell lines will be useful to evaluate the function of OCT4A transcription factor in the tumorigenic process in vivo, its involvement in the acquisition of tumor stem cell properties and the molecular changes associated with this phenotype (global gene expression and copy number aberration of chromosome segments). It is expected, with this study, to better understand how the aberrant expression of genes that control typical stem cell processes may promote cancer development, focusing on the role of OCT4A in a common type of primitive neuroectodermal tumor of embryonic origin. This study may also help identifying new molecular changes associated with tumor aggressiveness, as well as establishing a model for tumor stem cells that can be further explored to develop new therapies for this type of pediatric tumor of highly unfavorable clinical prognosis. (AU) | |