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

Grant number: 16/21785-4
Support type:Scholarships in Brazil - Post-Doctorate
Effective date (Start): September 01, 2017
Effective date (End): September 03, 2020
Field of knowledge:Health Sciences - Dentistry
Principal Investigator:Pablo Agustin Vargas
Grantee:Vivian Petersen Wagner
Home Institution: Faculdade de Odontologia de Piracicaba (FOP). Universidade Estadual de Campinas (UNICAMP). Piracicaba , SP, Brazil
Associated scholarship(s):18/15715-9 - Association of BDNF/TRKB signaling pathway with tumor agressiveness and cancer stem cell profile of salivary gland cancer, BE.EP.PD


Malignant salivary gland neoplasms (MSGN) represent a heterogeneous group of lesions with an incidence of 0,05-2 cases per 100.000 inhabitants annually. Mucoepidermoid carcinoma (MEC) and adenoid cystic carcinoma (ACC) are the more prevalent histologic types. Currently, there is a lack of an effective systemic therapy for these tumors leading to low survival rates for cases of disseminated disease. Therefore, it is very important to identify specific therapeutic targets that act on mechanisms associated with tumor progression and resistance to therapy. The signaling pathway of brain-derived neurotrophic factor (BDNF) and its tropomyosin receptor kinase B (TrkB) is associated with aggressiveness in different types of solid tumors, including breast, colorectal and lung cancer. The evidences demonstrate that this pathway stimulates the epithelial-mesenchymal transition and the fraction of cancer stem cells (CSC), making this pathway a promising therapeutic target. It is now known that the CSC population present resistance mechanisms to evade conventional therapies and are the main responsible for post-treatment metastasis or relapse. In MSGN the role of BDNF/TrkBpathway and it's association with CSC the population remains unclear. Therefore, the objective of the present project is to identify the association of this pathway with tumor aggressiveness and CSC profile in tissue samples and cell lines of ACC and MEC. Theexpression of proteins involved in the signaling pathway of BDNF / TrkB will be assessed by immunohistochemistry in MEC and ACC cases previously collected. The results will be compared with clinical data and with the expression of genes related to a CSC profile (BMI-1, CD44, Nanog) measured by PCR. Cell lines of ACC and MEC will be treated with BDNF stimulation or TrkB inhibition isolated or associated with cisplatin. The expression of proteins involved in the BDNF/TrkB signaling pathway will be assessed by western blot. The migratory and invasive capacity of cells will be evaluated as well as the presence of CSC through spheres assay and enzymatic activity of ALDH measured by flow cytometry. With this project we intend to identify a new therapeutic target for the most prevalent NMGS and present solid pre-clinical evidences regarding the efficacy of this therapy in cell culture. (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)
DE MORAES, JULIANA KERN; WAGNER, VIVIAN PETERSEN; FONSECA, FELIPE PAIVA; DO AMARAL-SILVA, GLEYSON KLEBER; DE FARIAS, CAROLINE BRUNETTO; SALLES PILAR, EMILY FERREIRA; GREGIANIN, AURO; ROESLER, RAFAEL; VARGAS, PABLO AGUSTIN; MARTINS, MANOELA DOMINGUES. Activation of BDNF/TrkB/Akt pathway is associated with aggressiveness and unfavorable survival in oral squamous cell carcinoma. ORAL DISEASES, v. 25, n. 8, p. 1925-1936, NOV 2019. Web of Science Citations: 0.

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