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Melanoma and chemoresistance: in vitro and in silico models to exploit therapeutic targets

Grant number: 17/04926-6
Support Opportunities:Research Projects - Thematic Grants
Duration: December 01, 2017 - November 30, 2022
Field of knowledge:Biological Sciences - Morphology - Cytology and Cell Biology
Principal Investigator:Silvya Stuchi Maria-Engler
Grantee:Silvya Stuchi Maria-Engler
Host Institution: Faculdade de Ciências Farmacêuticas (FCF). Universidade de São Paulo (USP). São Paulo , SP, Brazil
Associated researchers:Ana Campa ; Helder Takashi Imoto Nakaya ; Rui Manuel Vieira Reis ; Vinicius de Lima Vazquez
Associated scholarship(s):22/07596-5 - Evaluation of nickel toxicity in a reconstructed human epidermis model, BP.IC
22/08041-7 - Evaluation of the effect of conoidin A on the proliferative and invasive potential of NRAS mutant melanoma cells, BP.IC
20/14919-0 - Aging and response to chemotherapy during the treatment with collagen peptides: Reconstruction of aged human skin in vitro to study the invasion of melanoma resistant to treatment with B-RAF inhibitor, BP.DR
+ associated scholarships 20/14878-1 - The role of adenosine kinase in human Melanoma progression and resistance, BP.DD
20/15042-4 - Antiproliferative and cell invasion inhibitor potencial of new copper (II) complexes in human Melanoma with resistance to BRAF inhibitors phenotype, BP.DR
21/05150-7 - Oxidative metabolism in cultures of three-dimensional spheroids of melanoma resistant to BRAF inhibitor, BP.IC
19/07315-3 - The role of peroxiredoxins 1 and 2 in melanoma heterogeneity, BP.IC
19/11721-7 - Establishment of good cell culture practices for melanoma, BP.TT
18/20665-0 - The role of ADK gene in human melanoma cells, BP.MS
18/14936-1 - Mitochondrial metabolism dictates the heterogeneity and resistance of melanoma, BP.PD
18/17834-5 - Establishment of good practices for melanoma cell culture, BP.TT - associated scholarships

Abstract

Melanoma is a highly invasive and metastatic cancer, with high rates of mortality and chemoresistance. The MAPK pathway is constitutively activated, and there are already available powerful target-specific chemotherapeutics, such as BRAF inhibitors (vemurafenib and dabrafenib). However, resistance to BRAF inhibitors is observed after about 7 months of treatment, primarily because of the high degree of phenotypic, genetic and epigenetic intra-tumor heterogeneity. Although, combination therapies benefit patients, and immunotherapy has shown highly promising results, overcoming resistance remains major challenge. In silico screening studies from our laboratory using the TCGA and Gene Expression Omnibus (GEO) databases identified a collection of genes as being differentially expressed between invasive melanoma when compared with nevi (non-malignant lesion). Understanding the role and regulation of specifics genes should provide insights into the molecular mechanisms underpinning melanoma progression and ultimately resistance to therapy. In this study we will characterize the action of TOP1, ATP6V0B, ADK, PEMT and SINB3 genes in humans and vemurafenib-resistant Melanomas. This thematic project aim to complex process of the microenvironment, aging and metabolic process, and IDO and imune response. The objective is to identify target genes and mechanisms that contribute to vemurafenib resistance. To achieve this goal, the gene expression will be explored in a broad panel of human Melanomas at different stages of progression and mutation status, as well as in vemurafenib-sensitive and resistant cell lines. We will employ both monolayer culture and organotypic models that simulate invasion in reconstructed skin containing Melanoma, and explore histological samples from patients coming from a partnership with the Barretos Cancer Hospital. We will dissect the molecular pathways associated with these gene expression, as well as IDO, using gene manipulating tools (shRNA/CRISPR CAS9), and evaluate the impact of them on proliferation, migration, invasion, angiogenesis, and cell death induction. This study, like others already developed in our laboratory, can characterize genes that generate tumor subpopulations of resistant cells and aims at identifying pharmacologically tractable targets that may be used in combination to enhance therapeutic response. (AU)

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Scientific publications (14)
(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 SOUZA, NAYANE; DE OLIVEIRA, ERICA APARECIDA; FAIAO-FLORES, FERNANDA; PIMENTA, LUCIANA A.; QUINCOCES, JOSE A. P.; SAMPAIO, SANDRA C.; MARIA-ENGLER, SILVYA S.. Metalloproteinases Suppression Driven by the Curcumin Analog DM-1 Modulates Invasion in BRAF-Resistant Melanomas. ANTI-CANCER AGENTS IN MEDICINAL CHEMISTRY, v. 20, n. 9, p. 1038-1050, . (16/16554-3, 13/05172-4, 17/04926-6)
FERREIRA BRANQUINHO, MARYANA STEPHANY; BARROS SILVA, MAYSA BRAGA; CASTILHO, GABRIELA ANSANELO; CAVALCANTE, JACQUELINE; DE MORAES BARROS, SILVIA BERLANGA; CLARA, RENAN ORSATI; MARIA-ENGLER, SILVYA STUCHI; CAMPA, ANA. ynurenine inhibits melanogenesis in human melanocyte-keratinocyte co-cultures and in a reconstructed 3D skin mode. EXPERIMENTAL DERMATOLOGY, v. 31, n. 3, . (19/14527-7, 17/04926-6)
MALLAUPOMA CAMARENA, DENISSE ESTHER; ALCANTARA SEKIMOTO MATSUYAMA, LARISSA SATIKO; MARIA-ENGLER, SILVYA STUCHI; CATALANI, LUIZ HENRIQUE. Development of Epidermal Equivalent from Electrospun Synthetic Polymers for In Vitro Irritation/Corrosion Testing. NANOMATERIALS, v. 10, n. 12, . (11/21442-6, 18/13492-2, 17/04926-6, 19/14527-7)
ROCHA-BRITO, KARIN J. P.; CLERICI, STEFANO PIATTO; CORDEIRO, HELON GUIMARAES; SCOTA FERREIRA, AMANDA PETRINA; BARRETO FONSECA, EMANUELLA MARIA; GONCALVES, PAOLA R.; ABRANTES, JULIA LAURA F.; MILANI, RENATO; MASSARO, RENATO RAMOS; MARIA-ENGLER, SILVYA STUCHI; et al. uercetin increases mitochondrial proteins (VDAC and SDH) and downmodulates AXL and PIM-1 tyrosine kinase receptors in NRAS melanoma cell. Biological Chemistry, v. 403, n. 3, . (17/04926-6, 18/03593-6, 15/20412-7)
LIMA, FLAVIA A.; VILELA, RAQUEL V. R.; OREFICE, RODRIGO L.; SILVA, IZABELA R.; REIS, EDUARDO C. O.; CARVALHO, LARISSA A. C.; MARIA-ENGLER, SILVYA S.; FERREIRA, LUCAS A. M.; GOULART, GISELE A. C.. Nanostructured lipid carriers enhances the safety profile of tretinoin: in vitro and healthy human volunteers' studies. Nanomedicine, v. 16, n. 16, p. 1391-1409, . (17/04926-6, 18/14936-1)
VENANCIO, PALOMA ALMEIDA; LOPES CONSOLARO, MARCIA EDILAINE; DERCHAIN, SOPHIE FRANCOISE; BOCCARDO, ENRIQUE; VILLA, LUISA LINA; MARIA-ENGLER, SILVYA STUCHI; CAMPA, ANA; DISCACCIATI, MICHELLE GARCIA. Indoleamine 2,3-dioxygenase and tryptophan 2,3-dioxygenase expression in HPV infection, SILs, and cervical cancer. CANCER CYTOPATHOLOGY, v. 127, n. 9, . (12/09746-2, 17/04926-6)
HIEDA, DANIELE SEO; DA COSTA CARVALHO, LARISSA ANASTACIO; DE MELLO, BARBARA VAZ; DE OLIVEIRA, ERICA APARECIDA; DE ASSIS, SILVIA ROMANO; WU, JOANNA; DU-THUMM, LAURENCE; VIANA DA SILVA, CLAUDIA LARISSA; ROUBICEK, DEBORAH ARNSDORFF; MARIA-ENGLER, SILVYA STUCHI; et al. Air Particulate Matter Induces Skin Barrier Dysfunction and Water Transport Alteration on a Reconstructed Human Epidermis Model. JOURNAL OF INVESTIGATIVE DERMATOLOGY, v. 140, n. 12, p. 2343+, . (16/19963-1, 17/04926-6, 18/14936-1)
FERRAZ, LETICIA SILVA; DA COSTA, RENATA TORRES; DA COSTA, CLAUDIA ALVES; JOAO RIBEIRO, CESAR AUGUSTO; ARRUDA, DENISE COSTA; MARIA-ENGLER, SILVYA STUCHI; RODRIGUES, TIAGO. Targeting mitochondria in melanoma: Interplay between MAPK signaling pathway and mitochondrial dynamics. Biochemical Pharmacology, v. 178, . (18/11972-7, 18/25747-5, 17/04926-6, 15/25541-0)
DIOGENES SIENA, ADAMO DAVI; DE BARROS, ISABELA ICHIHARA; STORTI, CAMILA BALDIN; OLIVEIRA DE BIAGI JUNIOR, CARLOS ALBERTO; DA COSTA CARVALHO, LARISSA ANASTACIO; MARIA-ENGLER, SILVYA STUCHI; SOUSA, JOSANE DE FREITAS; SILVA JR, WILSON ARAUJO. pregulation of the novel lncRNA U731166 is associated with migration, invasion and vemurafenib resistance in melanom. JOURNAL OF CELLULAR AND MOLECULAR MEDICINE, v. 26, n. 3, p. 671-683, . (17/04926-6, 18/04017-9, 18/14936-1, 13/08135-2)
DE OLIVEIRA, ERICA APARECIDA; CHAUHAN, JAGAT; DA SILVA, JULIA REZENDE; DA COSTA CARVALHO, LARISSA ANASTACIO; DIAS, DIOGO; DE CARVALHO, DANIELLE GONCALVES; MASAO WATANABE, LUIS ROBERTO; REBECCA, VITO W.; MILLS, GORDON; LU, YILING; et al. TOP1 modulation during melanoma progression and in adaptative resistance to BRAF and MEK inhibitors. PHARMACOLOGICAL RESEARCH, v. 173, . (16/16554-3, 18/20665-0, 17/04926-6, 18/14936-1, 17/26148-5)
SANDRI, SILVANA; WATANABE, LUIS R. M.; DE OLIVEIRA, ERICA APARECIDA; FAIAO-FLORES, FERNANDA; MIGLIORINI, SILENE; TIAGO, MANOELA; FELIPE-SILVA, ALOISIO; VAZQUEZ, VINICIUS DE LIMA; SOUZA, PAOLA DA COSTA; LOPES CONSOLARO, MARCIA EDILAINE; et al. Indoleamine 2,3-dioxygenase in melanoma progression and BRAF inhibitor resistance. PHARMACOLOGICAL RESEARCH, v. 159, . (17/04926-6, 17/26148-5, 12/05910-2, 11/19045-9, 16/16554-3, 13/05172-4, 15/10821-7)
MINI, C. A.; DREOSSI, S. A. C.; ABE, F. R.; MARIA-ENGLER, S. S.; OLIVEIRA, D. P.. Immortalized keratinocytes cells generates an effective model of Epidermal Human Equivalent for irritation and corrosion tests. TOXICOLOGY IN VITRO, v. 71, . (16/15660-4, 17/04926-6, 19/14527-7)
ALVES-FERNANDES, DEBORA KRISTINA; DE OLIVEIRA, ERICA APARECIDA; HASTREITER, ARACELI APARECIDA; FAIAO-FLORES, FERNANDA; FELIPE-SILVA, ALOISIO SOUZA; TURATO, WALTER; FOCK, RICARDO AMBROSIO; MARIA-ENGLER, SILVYA STUCHI; DE MORAES BARROS, SILVIA BERLANGA. In vivo antitumoral effect of 4-nerolidylcatechol (4-NC) in NRAS-mutant human melanoma. Food and Chemical Toxicology, v. 141, . (17/07010-2, 14/24400-0, 14/06959-0, 17/04926-6)
ALVES-FERNANDES, DEBORA KRISTINA; DE OLIVEIR, ERICA APARECIDA; FAIAO-FLORES, FERNANDA; ALICEA-REBECCA, GRETCHEN; WEERARATNA, ASHANI T.; SMALLEY, KEIRAN S. M.; DE MORAES BARROS, SILVIA BERLANGA; MARIA-ENGLER, SILVYA STUCHI. ER stress promotes antitumor effects in BRAFi/MEKi resistant human melanoma induced by natural compound 4-nerolidylcathecol (4-NC). PHARMACOLOGICAL RESEARCH, v. 141, p. 63-72, . (17/07010-2, 14/24400-0, 14/06959-0, 17/04926-6)

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