Sandra Martha Gomes Dias
Researcher, Group Leader, LNBio-CNPEM
Phone: +55 19 3512.1267
Oncogenes and tumor suppressors regulate several enzymes of the biosynthetic and bioenergetic metabolic pathways, among which many of them shown to be crucial for cancer initiation and progression. Therefore, metabolic pathways are interesting targets against cancer. Aerobic glycolysis (or the Warburg effect) and high levels of glutaminolysis constitute metabolic hallmarks of most tumors and both are required to maintain cancer cell proliferative capacity.
Tumor cells consume glutamine at unusually high rates and glutamine metabolism has proven essential for the neoplastic transformation since its inhibition decreases cell proliferation. In this context, our current focus of research lays on the glutaminase, the enzyme that catalyses the conversion of glutamine to glutamate and is key for the generation of anaplerotic carbon for the TCA cycle. Moreover, we are also interested in understanding the cancer metabolic adaptation process through a broader point of view using tools such as transcriptomics and metabolomics, as a mean of finding new targets for cancer treatment.
Cellular and Biochemical Studies of the Glutaminase and Its Relation with Cancer
The transcription factors myc, HIF-1 and the PI3K/AKT/mTOR signaling pathway have been involved on the superactivation of the glycolytic pathway enzymes and on the truncation of the tricarboxilic acid cycle (TCA). However very little is known regarding how signaling pathways and transcription activators can promote the glutaminase activation in cells. In this regard, our goals are to study of the functional importance of the different isoforms of glutaminase, the biochemical and structural characterization of its potential binding partners and the understanding of how different signaling pathways can promote its activation. In addition, we are also focused in finding new inhibitory compounds of some of the glycolytic and glutaminolytic enzymes.
Transcriptomic and Metabolomic studies of cancer cells as a tool for understanding the metabolic adaptation process
The glutaminolytic and glycolytic pathways are the main generators of the metabolic precursors used for the synthesis of proteins, nucleic acids and lipids. There still remain several questions regarding how these two pathways are coordinated in order to ensure the continuous proliferation phenotype of tumors. The objective of this project is to use transcriptomics and metabolomics tools to understand the particular metabolic background of triple-negative breast cancer cells, as well as the cellular stress induced by some oncogenes from a metabolic point of view. In a broader perspective, new genes and new isoforms important for these processes can be recognized, which can lead to the proposal of new forms of therapeutic intervention.
Cassago, A. ; Ferreira, A. P. S. ; Ferreira, I. M. ; Fornezari, C. ; Gomes, E. R. M. ; Greene, K. S. ; Pereira, H. M. ; Garratt, R. C. ; Dias, S. M. G. ; Ambrosio, A. L. B. . Mitochondrial localization and structure-based phosphate activation mechanism of Glutaminase C with implications for cancer metabolism. PNAS, v.109, p. 1092-1097, 2012.
WANG, J. ; Erickson, JW ; Fuji, Reina ; Ramachandran, S ; Gao, Ping ; Dinavahi, Ramani ; Wilson, Kristin F ; Ambrosio, A.L. ; Dias, S. M. G. ; Dang, Chi V. ; Cerione, R.A. . Targeting mitochondrial glutaminase activity inhibits oncogenic transformation.. Cancer Cell, v. 18, p. 207-219, 2010.
DIAS, S. M. G. ; Wilson, K.F. ; Rojas, K.S. ; Ambrosio, A.L. ; Cerione, R.A. The molecular basis for the regulation of the cap-binding complex by the importins. Nature Structural & Molecular Biology (Online), v. 16, p. 930-937, 2009.
Martinez, L. ; Nascimento, A. S. ; Nunes, F. M. ; Phillips, K. ; Aparicio, R. ; DIAS, S. M. G. ; Figueira, A. C. M. ; Lin, J. H. ; Nguyen, P. ; Apriletti, J. W. ; Neves, F. A. R. ; Baxter, J. D. ; Webb, P. ; Skaf, M. S. ; Polikarpov, I. . Gaining ligand selectivity in thyroid hormone receptors via entropy. Proceedings of the National Academy of Sciences of the United States of America, v. 106, p. 20717-20722, 2009.
Ambrosio, A.L. ; DIAS, S. M. G. ou DIAS, S. M. ; Polikarpov, I. ; Zurier, R.B. ; Burstein, S.H.; Garratt, R.C. . Ajulemic acid, a synthetic nonpsychoactive cannabinoid acid, bound to the ligand binding domain of the human peroxisome proliferator activated receptor gamma. Journal of Biological Chemistry (Online), v. 282, p. 18625-18633, 2007.
Ph.D. Applied Physics – specialization in Biomolecular Physics 2004, Institute of Physics of São Carlos, University of São Paulo, Brazil. Thesis advisor: Igor Polikarpov; “Structural Studies of the Human Thyroid Hormone Receptor Isoform β1 (hTRβ) and the Human 9-cis Receptor Isoform α (hRXRα1)”.
MSc Biological Sciences – specialization in Plant Molecular Genetics 1999, Campinas State University (UNICAMP), Brazil. Thesis advisor: Anete Pereira de Souza; “Identification and characterization of the trnS/pseudo-tRNA/nad3/rps12 gene cluster from Coix lacryma-jobi L: organization, transcription and RNA editing”.
Bachelor Degree in Biological Sciences – specialization in Molecular Biology 1996, Campinas State University (UNICAMP), Brazil
Young Researcher Fellowship (Feb 2010-Oct 2010) awarded by Sao Paulo Research Foundation (Fundação de Amparo a Pesquisa do Estado de São Paulo – FAPESP)
Associate Research to Richard Ceriones`s laboratory (2008 – 2009) Molecular Medicine Department Veterinary Medical Center, Cornell University, Ithaca, NY- USA
Post Doctoral Associated to Richard Ceriones`s laboratory (2005 – 2008) at Molecular Medicine Department, Veterinary Medical Center, Cornell University, Ithaca, NY- USA.