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Association of BDNF/TRKB signaling pathway with tumor agressiveness and cancer stem cell profile of salivary gland cancer

Grant number: 18/15715-9
Support type:Scholarships abroad - Research Internship - Post-doctor
Effective date (Start): January 05, 2019
Effective date (End): January 04, 2020
Field of knowledge:Health Sciences - Dentistry
Principal Investigator:Pablo Agustin Vargas
Grantee:Vivian Petersen Wagner
Supervisor abroad: Lynne Bingle
Home Institution: Faculdade de Odontologia de Piracicaba (FOP). Universidade Estadual de Campinas (UNICAMP). Piracicaba , SP, Brazil
Local de pesquisa : University of Sheffield, England  
Associated to the scholarship:16/21785-4 - Association of BDNF/TRKB signaling pathway with tumor agressiveness and cancer stem cell profile of malignant salivary gland tumors, BP.PD

Abstract

Mucoepidermoid carcinoma (MEC) represents the most prevalent histologic type of salivary gland cancer (SGC). This tumor frequently carries a consistent translocation involving the CRTC1 and MAML2 genes. Currently, all drug-based therapies to MEC are considered merely palliative. The signaling pathway of brain-derived neurotrophic factor (BDNF) and its tropomyosin receptor kinase B (TrkB) is associated with aggressiveness and the presence of cancer stem cells (CSC) in several types of solid tumors, such as breast and prostate cancer, medulloblastoma and head and neck squamous cell carcinoma. In MEC the role of the BDNF/TrkB pathway as a therapeutic target remains to be elucidated. Moreover, it is not clear if the presence of the CRTC1-MAML2 translocation influences the activation of this pathway. The main objective of the present study is to assess the effect of a TrkB inhibitor (ANA-12) alone, or in association with cisplatin, in the oncogenic potential of MEC cells. The second objective of our proposal is to correlate the presence of the CRTC1-MAML2 translocation with the expression of BDNF/TrkB proteins in MEC tumor samples. MEC cell lines will be treated with ANA-12 (alone or in association with cisplatin) and the expression of BDNF/TrkB signaling pathway proteins will be assessed by western blotting. The migratory and invasive capacity of cells will be evaluated respectively by a scratch assay and invasion assay using transwell chambers. The presence of CSC will be assessed through a spheroid assay and enzymatic activity of aldehyde dehydrogenase (ALDH) measured by flow cytometry. MEC tumor samples will be evaluated for the presence of the CRTC1-MAML2 translocation through fluorescence in situ hybridization and immunohistochemistry and the results will be compared with the immunoexpression of BDNF, phospho-TrkB and two downstream targets of these activation, phospho-Akt and phospho-ribossomal protein S6.

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