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Characterization of the melatonergic system of human gliomas and its implication on tumor aggressiveness and invasiveness

Grant number: 14/27287-0
Support Opportunities:Scholarships in Brazil - Doctorate (Direct)
Effective date (Start): March 01, 2016
Effective date (End): August 24, 2019
Field of knowledge:Biological Sciences - Physiology - General Physiology
Principal Investigator:Pedro Augusto Carlos Magno Fernandes
Grantee:Gabriela Sarti Kinker
Host Institution: Instituto de Biociências (IB). Universidade de São Paulo (USP). São Paulo , SP, Brazil
Associated scholarship(s):17/24287-8 - The role of tumor microenvironment elements in malignant cell plasticity and heterogeneity, BE.EP.DD


Gliomas, the most frequent primary brain tumor in adults, are classified into four (I-IV) histological grades. Gliomas grade IV, known as glioblastomas, are highly aggressive tumors associated with a median survival of only 15 months. In vitro studies have shown that high concentrations of melatonin, a hormone synthesized mainly by the pineal gland, significantly reduce the migration and invasion of glioma cells lines. Additionally, in a preliminary study we observed a decreased expression of acetylserotonin O-methyltransferase (ASMT), the final enzyme of melatonin biosynthesis, in glioblastomas, compared to non-malignant tissue and low-grade gliomas. Based on these data, during my Scientific Initiation (SI) we demonstrated that the ability of human glioma cell lines (HOG, T98G and U87MG) to produce melatonin is inversely proportional to the grade of tumor invasiveness/aggressiveness. Moreover, the most aggressive cell line (U87MG) presented the highest expression of cytochrome P450 1B1 (CYP1B1), the gene encoding the main enzyme of melatonin metabolism in the central nervous system. Therefore, we raised the hypothesis that the melatonergic system of human gliomas is implicated on the determination of tumor invasiveness and aggressiveness. Accordingly, our aim is to: i) characterize the melatonergic system of glioma cell lines with different grades of invasiveness/aggressiveness (started in my SI) and human glioma biopsies; ii) evaluate the implication of glioma-synthesized melatonin on different aspects of tumor development and progression. Our future findings will not only contribute to the molecular pathology of gliomas, but will also lay some groundwork for the development of target therapies that consider the use of melatonin and analogous in the treatment of gliomas. (AU)

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Scientific publications (7)
(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)
MARKUS, REGINA P.; FERNANDES, PEDRO A.; KINKER, GABRIELA S.; CRUZ-MACHADO, SANSERAY DA SILVEIRA; MARCOLA, MARINA. Immune-pineal axis - acute inflammatory responses coordinate melatonin synthesis by pinealocytes and phagocytes. British Journal of Pharmacology, v. 175, n. 16, SI, p. 3239-3250, . (14/27287-0, 15/04557-5, 10/52687-1, 13/13691-1)
KINKER, G. S.; OSTROWSKI, L. H.; RIBEIRO, P. A. C.; CHANOCH, R.; MUXEL, S. M.; TIROSH, I.; SPADONI, G.; RIVARA, S.; MARTINS, V. R.; SANTOS, T. G.; et al. MT1 and MT2 melatonin receptors play opposite roles in brain cancer progression. JOURNAL OF MOLECULAR MEDICINE-JMM, v. 99, n. 2, . (14/23830-1, 14/27287-0, 13/13691-1, 17/24287-8, 14/50943-1, 15/23348-8)
MONTEIRO DE ASSIS, LEONARDO VINICIUS; MENDES, DAVI; SILVA, MATHEUS MOLINA; KINKER, GABRIELA SARTI; PEREIRA-LIMA, ISABELLA; MORAES, MARIA NATHALIA; MARTINS MENCK, CARLOS FREDERICO; DE LAURO CASTRUCCI, ANA MARIA. Melanopsin mediates UVA-dependent modulation of proliferation, pigmentation, apoptosis, and molecular clock in normal and malignant melanocytes. BIOCHIMICA ET BIOPHYSICA ACTA-MOLECULAR CELL RESEARCH, v. 1867, n. 10, . (14/27287-0, 19/19435-3, 13/24337-4, 17/24615-5, 12/50214-4, 18/16511-8, 17/26651-9, 17/18781-0, 18/14728-0, 17/24217-0)
KINKER, GABRIELA S.; GREENWALD, ALISSA C.; TAL, ROTEM; ORLOVA, ZHANNA; CUOCO, MICHAEL S.; MCFARLAND, JAMES M.; WARREN, ALLISON; RODMAN, CHRISTOPHER; ROTH, JENNIFER A.; BENDER, SAMANTHA A.; et al. Pan-cancer single-cell RNA-seq identifies recurring programs of cellular heterogeneity. Nature Genetics, v. 52, n. 11, p. 1208+, . (17/24287-8, 14/27287-0)
MONTEIRO DE ASSIS, LEONARDO VINICIUS; KINKER, GABRIELA SARTI; MORAES, MARIA NATHALIA; MARKUS, REGINA P.; FERNANDES, PEDRO AUGUSTO; DE LAURO CASTRUCCI, ANA MARIA. Expression of the Circadian Clock Gene BMAL1 Positively Correlates With Antitumor Immunity and Patient Survival in Metastatic Melanoma. FRONTIERS IN ONCOLOGY, v. 8, . (13/24337-4, 14/27287-0, 12/50214-4, 14/16412-9)
KINKER, GABRIELA SARTI; THOMAS, ANDREW MALTEZ; CARVALHO, VINICIUS JARDIM; LIMA, FELIPE PRATA; FUJITA, ANDRE. Deletion and low expression of NFKBIA are associated with poor prognosis in lower-grade glioma patients. SCIENTIFIC REPORTS, v. 6, . (14/27287-0, 15/01507-7, 15/01587-0, 13/03447-6, 14/09576-5)
HARA, TOSHIRO; CHANOCH-MYERS, RONY; MATHEWSON, NATHAN D.; MYSKIW, CHAD; ATTA, LYLA; BUSSEMA, LILLIAN; EICHHORN, STEPHEN W.; GREENWALD, ALISSA C.; KINKER, GABRIELA S.; RODMAN, CHRISTOPHER; et al. Interactions between cancer cells and immune cells drive transitions to mesenchymal-like states in glioblastoma. CANCER CELL, v. 39, n. 6, p. 779+, . (14/27287-0, 17/24287-8)
Academic Publications
(References retrieved automatically from State of São Paulo Research Institutions)
KINKER, Gabriela Sarti. Causes and consequences of intratumoral cellular heterogeneity and the role of the melatonergic system in brain tumors. 2019. Doctoral Thesis - Universidade de São Paulo (USP). Instituto de Biociências (IBIOC/SB) São Paulo.

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