ALOISIO SOUZA FELIPE DA SILVA
Projetos de Pesquisa
Unidades Organizacionais
Departamento de Patologia, Faculdade de Medicina - Docente
SVANPA-62, Hospital Universitário
LIM/14 - Laboratório de Investigação em Patologia Hepática, Hospital das Clínicas, Faculdade de Medicina
SVANPA-62, Hospital Universitário
LIM/14 - Laboratório de Investigação em Patologia Hepática, Hospital das Clínicas, Faculdade de Medicina
2 resultados
Resultados de Busca
Agora exibindo 1 - 2 de 2
- Indoleamine 2,3-dioxygenase in melanoma progression and BRAF inhibitor resistance(2020) SANDRI, Silvana; WATANABE, Luis R. M.; OLIVEIRA, Erica Aparecida de; FAIAO-FLORES, Fernanda; MIGLIORINI, Silene; TIAGO, Manoela; FELIPE-SILVA, Aloisio; VAZQUEZ, Vinicius de Lima; SOUZA, Paola da Costa; CONSOLARO, Marcia Edilaine Lopes; CAMPA, Ana; MARIA-ENGLER, Silvya StuchiIndoleamine 2,3-dioxygenase (IDO) is associated with the progression of many types of tumors, including melanoma. However, there is limited information about IDO modulation on tumor cell itself and the effect of BRAF inhibitor (BRAFi) treatment and resistance. Herein, IDO expression was analyzed in different stages of melanoma development and progression linked to BRAFi resistance. IDO expression was increased in primary and metastatic melanomas from patients' biopsies, especially in the immune cells infiltrate. Using a bioinformatics approach, we also identified an increase in the IDO mRNA in the vertical growth and metastatic phases of melanoma. Using in silico analyses, we found that IDO mRNA was increased in BRAFi resistance. In an in vitro model, IDO expression and activity induced by interferon-gamma (IFN gamma) in sensitive melanoma cells was decreased by BRAFi treatment. However, cells that became resistant to BRAFi presented random IDO expression levels. Also, we identified that treatment with the IDO inhibitor, 1-methyltryptophan (1-MT), was able to reduce clonogenicity for parental and BRAFi-resistant cells. In conclusion, our results support the hypothesis that the decreased IDO expression in tumor cells is one of the many additional outcomes contributing to the therapeutic effects of BRAFi. Still, the IDO production changeability by the BRAFi-resistant cells reiterates the complexity of the response arising from resistance, making it not possible, at this stage, to associate IDO expression in tumor cells with resistance. On the other hand, the maintenance of 1-MT off-target effect endorses its use as an adjuvant treatment of melanoma that has become BRAFi-resistant.
- TOP1 modulation during melanoma progression and in adaptative resistance to BRAF and MEK inhibitors(2021) OLIVEIRA, Erica Aparecida de; CHAUHAN, Jagat; SILVA, Julia Rezende da; CARVALHO, Larissa Anastacio da Costa; DIAS, Diogo; CARVALHO, Danielle Goncalves de; WATANABE, Luis Roberto Masao; REBECCA, Vito W.; MILLS, Gordon; LU, Yiling; SILVA, Aloisio Souza Felipe da; CONSOLARO, Marcia Edilaine Lopes; HERLYN, Meenhard; POSSIK, Patricia A.; GODING, Colin R.; MARIA-ENGLER, Silvya StuchiIn melanomas, therapy resistance can arise due to a combination of genetic, epigenetic and phenotypic mechanisms. Due to its crucial role in DNA supercoil relaxation, TOP1 is often considered an essential chemotherapeutic target in cancer. However, how TOP1 expression and activity might differ in therapy sensitive versus resistant cell types is unknown. Here we show that TOP1 expression is increased in metastatic melanoma and correlates with an invasive gene expression signature. More specifically, TOP1 expression is highest in cells with the lowest expression of MITF, a key regulator of melanoma biology. Notably, TOP1 and DNA Single-Strand Break Repair genes are downregulated in BRAFi- and BRAFi/MEKi-resistant cells and TOP1 inhibition decreases invasion markers only in BRAFi/MEKi-resistant cells. Thus, we show three different phenotypes related to TOP1 levels: i) non-malignant cells with low TOP1 levels; ii) metastatic cells with high TOP1 levels and high invasiveness; and iii) BRAFi- and BRAFi/MEKi-resistant cells with low TOP1 levels and high invasiveness. Together, these results highlight the potential role of TOP1 in melanoma progression and resistance.