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 Opportunities: Scholarships in Brazil - Post-Doctoral
• 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
• Host 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

Abstract

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

(16)

(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)

SCHUCH, LAUREN FRENZEL; KOVALSKI, LUAN NATHIEL SANTANA; LEITE, AMANDA ALMEIDA; CARRARD, VINICIUS COELHO; MARTINS, MARCO ANTONIO TREVIZANI; VARGAS, PABLO AGUSTIN; MARTINS, MANOELA DOMINGUES. Oral lymphangioma-like Kaposi sarcoma: a Brazilian case report in a scenario of a still high number of HIV infections. ORAL AND MAXILLOFACIAL SURGERY-HEIDELBERG, JUN 2021. (16/21785-4)

WAGNER, VIVIAN P.; MARTINS, MANOELA D.; AMOURA, ESRA; ZANELLA, VIRGILIO G.; ROESLER, RAFAEL; DE FARIAS, CAROLINE B.; BINGLE, COLIN D.; VARGAS, PABLO A.; BINGLE, LYNNE. TrkB-Targeted Therapy for Mucoepidermoid Carcinoma. BIOMEDICINES, v. 8, n. 12, DEC 2020. (18/15715-9, 16/21785-4)

KIRSCHNICK, LAURA BORGES; SILVEIRA, FELIPE MARTINS; SCHUCH, LAUREN FRENZEL; FONSECA, FELIPE PAIVA; MARTINS, MARCO ANTONIO TREVIZANI; LOPES, MARCIO AJUDARTE; SANTOS-SILVA, ALAN ROGER; CARRARD, VINICIUS COELHO; DOS SANTOS, JEAN NUNES; VARGAS, PABLO AGUSTIN; et al. Clinicopathological analysis of oral and maxillofacial acinic cell carcinoma: A systematic review. JOURNAL OF ORAL PATHOLOGY & MEDICINE, v. 50, n. 8, p. 741-749, SEP 2021. (16/21785-4)

ARIOTTI, C.; GABRIEL, A. F.; RIBEIRO, J. T.; MARTINS, M. A. T.; VARGAS, P. A.; PILAR, E. F. S.; CASTILHO, R. M.; CARRARD, V. C.; WAGNER, V. P.; MARTINS, M. D.. PI3K/AKT/mTOR pathway activation in actinic cheilitis and lip squamous cell carcinomas. JOURNAL OF THE EUROPEAN ACADEMY OF DERMATOLOGY AND VENEREOLOGY, v. 34, n. 9, JUN 2020. (16/21785-4)

SCHUCH, LAUREN F.; SILVEIRA, FELIPE M.; WAGNER, VIVIAN P.; BORGATO, GABRIELL B.; ROCHA, GUILHERME Z.; CASTILHO, ROGERIO M.; VARGAS, PABLO A.; MARTINS, MANOELA D.. Head and neck cancer patient-derived xenograft models - A systematic review. CRITICAL REVIEWS IN ONCOLOGY HEMATOLOGY, v. 155, NOV 2020. (16/21785-4)

GIRARDI, FABIO MURADAS; WAGNER, VIVIAN PETERSEN; MARTINS, MANOELA DOMINGUES; ABENTROTH, ALIENDE LENGLER; HAUTH, LUIZ ALBERTO. Melhor desfecho para metástase da parótida vs. cervical de carcinoma espinocelular cutâneo de cabeça e pescoço: um novo informe sobre dados reemergentes. Brazilian Journal of Otorhinolaryngology, v. 87, n. 4, p. 389-395, JUL-AUG 2021. (16/21785-4)

SILVEIRA, FELIPE MARTINS; SCHMIDT, TUANY RAFAELI; NEUMANN, BRUNA; ROSSET, CLEVIA; ZANELLA, VIRGILIO GONZALES; MAAHS, GERSON SCHULZ; TREVIZANI MARTINS, MARCO ANTONIO; ARANY, PRAVEEN; WAGNER, VIVIAN PETERSEN; LOPES, MARCIO AJUDARTE; et al. Impact of photobiomodulation in a patient-derived xenograft model of oral squamous cell carcinoma. ORAL DISEASES, JUL 2021. (18/02233-6, 16/21785-4)

WAGNER, VIVIAN PETERSEN; RODRIGUES-FERNANDES, CARLA ISABELLY; RIBEIRO CARVALHO, MARCUS VINICIUS; SANTOS, JEAN NUNES; BARRA, MARINEZ BIZARRO; HUNTER, KEITH D.; MANUEL AGUIRR-URIZAR, JOSE; HEERDEN, WILLIE F. P.; VARGAS, PABLO AGUSTIN; FONSECA, FELIPE PAIVA; et al. Mantle cell lymphoma, malt lymphoma, small lymphocytic lymphoma, and follicular lymphoma of the oral cavity: An update. JOURNAL OF ORAL PATHOLOGY & MEDICINE, v. 50, n. 6, p. 622-630, JUL 2021. (16/21785-4)

KIRSCHNICK, LAURA BORGES; SILVEIRA, FELIPE MARTINS; SCHUCH, LAUREN FRENZEL; FONSECA, FELIPE PAIVA; MARTINS, MARCO ANTONIO TREVIZANI; LOPES, MARCIO AJUDARTE; SANTOS-SILVA, ALAN ROGER; CARRARD, VINICIUS COELHO; DOS SANTOS, JEAN NUNES; VARGAS, PABLO AGUSTIN; et al. Clinicopathological analysis of oral and maxillofacial acinic cell carcinoma: A systematic review. JOURNAL OF ORAL PATHOLOGY & MEDICINE, FEB 2021. (16/21785-4)

SCHUCH, LAUREN FRENZEL; KOVALSKI, LUAN NATHIEL SANTANA; LEITE, AMANDA ALMEIDA; CARRARD, VINICIUS COELHO; MARTINS, MARCO ANTONIO TREVIZANI; VARGAS, PABLO AGUSTIN; MARTINS, MANOELA DOMINGUES. Oral lymphangioma-like Kaposi sarcoma: a Brazilian case report in a scenario of a still high number of HIV infections. ORAL AND MAXILLOFACIAL SURGERY-HEIDELBERG, v. 26, n. 1, p. 6-pg., 2021-06-05. (16/21785-4)

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. (16/21785-4)

GIRARDI, FABIO MURADAS; WAGNER, VIVIAN P.; MARTINS, MANOELA DOMINGUES; ABENTROTH, ALIENDE LENGLER; HAUTH, LUIZ ALBERTO. Prevalence of p16 expression in oropharyngeal squamous cell carcinoma in southern Brazil. ORAL SURGERY ORAL MEDICINE ORAL PATHOLOGY ORAL RADIOLOGY, v. 130, n. 6, p. 681-691, DEC 2020. (16/21785-4)

BROCHADO, FERNANDA THOME; MARMORA, BELKISS CAMARA; CAMPOS, PALOMA SANTOS; SCHMIDT, TUANY RAFAELI; SANTOS FERNANDES, KRISTIANNE PORTA; BUSSADORI, SANDRA KALIL; SANTOS, LUCAS GONCALVES; WAGNER, VIVIAN PETERSEN; LAMERS, MARCELO LAZZARON; MARTINS, MANOELA DOMINGUES. Effects of different protocols of defocused high-power laser on the viability and migration of myoblasts-a comparative in vitro study. Lasers in Medical Science, v. 37, n. 9, p. 11-pg., 2022-09-20. (16/21785-4)

SILVA, LUAN CESAR; BORGATO, GABRIELL BONIFACIO; WAGNER, VIVIAN PETERSEN; MARTINS, MANOELA DOMINGUES; ROCHA, GUILHERME ZWEIG; LOPES, MARCIO AJUDARTE; SANTOS-SILVA, ALAN ROGER; DE CASTRO JUNIOR, GILBERTO; KOWALSKI, LUIZ PAULO; NOR, JACQUES E.; et al. Cephaeline is an inductor of histone H3 acetylation and inhibitor of mucoepidermoid carcinoma cancer stem cells. JOURNAL OF ORAL PATHOLOGY & MEDICINE, OCT 2021. (19/06597-5, 16/05710-4, 16/21785-4)

ZANELLA, VIRGILIO GONZALES; WAGNER, VIVIAN PETERSEN; SCHMIDT, MANY RAFAELI; THIEME, STEFANIE; CORREA, CINTIA; FONSECA, FELIPE PAIVA; RIGON, PETTALA; BARRA, MARINEZ BIZARRO; KROEF, RICARDO GALLICCHIO; VARGAS, PABLO AGUSTIN; et al. Salivary gland cancer in Southern Brazil: a prognostic study of 107 cases. MEDICINA ORAL PATOLOGIA ORAL Y CIRUGIA BUCAL, v. 26, n. 3, p. 11-pg., 2021-05-01. (16/21785-4)

DO AMARAL-SILVA, GLEYSON KLEBER; DIAS, LARYSSA MOURA; LINHARES ALMEIDA MARIZ, BRUNO AUGUSTO; FONSECA, FELIPE PAIVA; CARRINHO AYROZA RANGEL, ANA LUCIA; ZANELLA, VIRGILIO GONZALES; CASTILHO, ROGERIO MORAES; MARTINS, MANOELA DOMINGUES; VARGAS, PABLO AGUSTIN; WAGNER, VIVIAN PETERSEN. MutS alpha expression predicts a lower disease-free survival in malignant salivary gland tumors: an immunohistochemical study. MEDICINA ORAL PATOLOGIA ORAL Y CIRUGIA BUCAL, v. 27, n. 2, p. 10-pg., 2022-03-01. (09/53839-2, 17/08995-2, 18/12435-5, 15/21520-8, 16/21785-4, 18/24715-2)