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Relevance of ADAM23-dependent modulation of Wnt signaling to glioma progression

Grant number: 14/04945-2
Support type:Scholarships abroad - Research Internship - Post-doctor
Effective date (Start): April 28, 2014
Effective date (End): April 27, 2015
Field of knowledge:Biological Sciences - Genetics
Principal Investigator:Érico Tosoni Costa
Grantee:Gabriela Filoso Barnabé
Supervisor abroad: Frank B. Furnari
Home Institution: Laboratório de Biologia Molecular e Genômica. Instituto Ludwig de Pesquisa sobre o Câncer (ILPC). São Paulo , SP, Brazil
Local de pesquisa : Ludwig Institute for Cancer Research, San Diego, United States  

Abstract

Malignant phenotype evolves through a fine-tuning of certain inherent molecular programs. Within this context, epigenetic silencing of ADAM23 gene arises as a recurrent event in a wide range of tumors, frequently associated with metastatic disease and/or tumor progression. We show that ADAM23 expression is gradually downregulated during glioma progression compared to normal brain samples, which is in accordance with the notion that ADAM23 downregulation might be ubiquitously associated with the activation of malignant programs in cancer cells. We have supportive data from RNA-Seq indicating that ADAM23 knockdown activates the WNT pathway, which is involved in control of cell movement and cell fate determination. Additionally, ADAM23-knocked down cells also can instruct non-silenced ADAM23-positive neighbor cells towards a more migratory and invasive phenotype in our cell model (MDA-MB-435), a crosstalk mediated by nitric oxide (NO). Then, to test whether WNT pathway activation dependent on ADAM23 silencing accounts for glioblastoma (GBM) malignancy, we propose to knockdown ADAM23 in GBM cell lines, characterize some main regulators of the WNT pathway by Western Blot, and then use drugs or shRNA constructs to activate or inhibit specific regulators of WNT signaling cascade. We expect to identify which perturbations on canonical or non-canonical WNT signaling could abrogate either intrinsic or extrinsic ADAM23-knockdown-derived effects. Also, the use of neurospheres cultures from glioma samples could be an interesting model to access the stem-like phenotype associated to ADAM23 downregulation. Alternatively, we are going to explore the activation of other malignant programs in the heterogeneous context, such as Notch and Hedgehog, which can also be modulated by NO signaling. We believe that the collaboration with Dr. Frank Furnari's group at Ludwig Institute for Cancer Research (San Diego, CA, USA) is going to be essential to further assign a driving role for ADAM23 downregulation in astrocytoma progression and malignancy. (AU)