PAULA RODRIGUES SOLA
Projetos de Pesquisa
Unidades Organizacionais
Departamento de Neurologia, Faculdade de Medicina
LIM/15 - Laboratório de Investigação em Neurologia, Hospital das Clínicas, Faculdade de Medicina
LIM/15 - Laboratório de Investigação em Neurologia, Hospital das Clínicas, Faculdade de Medicina
11 resultados
Resultados de Busca
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- Impact of a cell cycle and an extracellular matrix remodeling transcriptional signature on tumor progression and correlation with EZH2 expression in meningioma(2022) PEREIRA, Benedito Jamilson Araujo; LERARIO, Antonio Marcondes; SOLA, Paula Rodrigues; LAURENTINO, Talita de Sousa; MOHAN, Dipika R.; ALMEIDA, Antonio Nogueira de; AGUIAR, Paulo Henrique Pires de; PAIVA, Wellingson da Silva; WAKAMATSU, Alda; TEIXEIRA, Manoel Jacobsen; OBA-SHINJO, Sueli Mieko; MARIE, Suely Kazue NagahashiOBJECTIVE The authors searched for genetic and transcriptional signatures associated with tumor progression and recurrence in their cohort of patients with meningiomas, combining the analysis of targeted exome, NF2-LOH, transcrip-tome, and protein expressions. METHODS The authors included 91 patients who underwent resection of intracranial meningioma at their institution between June 2000 and November 2007. The search of somatic mutations was performed by Next Generation Sequenc-ing through a customized panel and multiplex ligation-dependent probe amplification for NF2 loss of heterozygosity. The transcriptomic profile was analyzed by QuantSeq 3 ' mRNA-Seq. The differentially expressed genes of interest were validated at the protein level analysis by immunohistochemistry.RESULTS The transcriptomic analysis identified an upregulated set of genes related to metabolism and cell cycle and downregulated genes related to immune response and extracellular matrix remodeling in grade 2 (atypical) meningio-mas, with a significant difference in recurrent compared with nonrecurrent cases. EZH2 nuclear positivity associated with grade 2, particularly with recurrent tumors and EZH2 gene expression level, correlated positively with the expres-sion of genes related to cell cycle and negatively to genes related to immune response and regulation of cell motility. CONCLUSIONS The authors identified modules of dysregulated genes in grade 2 meningiomas related to the activation of oxidative metabolism, cell division, cell motility due to extracellular remodeling, and immune evasion that were predic-tive of survival and exhibited significant correlations with EZH2 expression.
- Transcriptomic analysis of purified human cortical microglia reveals age-associated changes(2017) GALATRO, Thais F.; HOLTMAN, Inge R.; LERARIO, Antonio M.; VAINCHTEIN, Ilia D.; BROUWER, Nieske; SOLA, Paula R.; VERAS, Mariana M.; PEREIRA, Tulio F.; LEITE, Renata E. P.; MOLLER, Thomas; WES, Paul D.; SOGAYAR, Mari C.; LAMAN, Jon D.; DUNNEN, Wilfred den; PASQUALUCCI, Carlos A.; OBA-SHINJO, Sueli M.; BODDEKE, Erik W. G. M.; MARIE, Suely K. N.; EGGEN, Bart J. L.Microglia are essential for CNS homeostasis and innate neuroimmune function, and play important roles in neurodegeneration and brain aging. Here we present gene expression profiles of purified microglia isolated at autopsy from the parietal cortex of 39 human subjects with intact cognition. Overall, genes expressed by human microglia were similar to those in mouse, including established microglial genes CX3CR1, P2RY12 and ITGAM (CD11B). However, a number of immune genes, not identified as part of the mouse microglial signature, were abundantly expressed in human microglia, including TLR, F-c gamma and SIGLEC receptors, as well as TAL1 and IFI16, regulators of proliferation and cell cycle. Age-associated changes in human microglia were enriched for genes involved in cell adhesion, axonal guidance, cell surface receptor expression and actin (dis)assembly. Limited overlap was observed in microglial genes regulated during aging between mice and humans, indicating that human and mouse microglia age differently.
conferenceObject Microglia exhibits proliferative and ECM modulating profiles in human gliomas(2017) GALATRO, T. F. de Almeida; LERARIO, A.; MORETTI, I.; SOLA, P.; BERTOLDI, E. R.; FREITAS, V. G.; PEREIRA, T.; MARTINEZ, R. C.; MALDAUN, M. V.; EGGEN, B. J. L.; MARIE, S. K.- ATRX-DAXX Complex Expression Levels and Telomere Length in Normal Young and Elder Autopsy Human Brains(2019) CAVALCANTE, Stella G.; SILVA, Clarisse P. N.; SOLA, Paula R.; TANAKA, Leonardo Y.; OBA-SHINJO, Sueli M.; MARIE, Suely K. N.The chromatin-remodeling complex ATRX/DAXX is one of the major epigenetic factors that controls heterochromatin maintenance due to its role in histone deposition. ATRX is involved in nucleosome configuration and maintenance of higher order chromatin structure, and DAXX is a specific histone chaperone for H3.3 deposition. Dysfunctions in this complex have been associated with telomere shortening, which influences cell senescence. However, data about this complex in brain tissue related to aging are still scarce. Therefore, in the present study, we analyzed ATRX and DAXX expressions in autopsied human brain specimens and the telomere length. A significant decrease in gene and protein expressions was observed in the brain tissues from the elderly compared with those from the young, which were related to short telomeres. These findings may motivate further functional analysis to confirm the ATRX-DAXX complex involvement in telomere maintenance and brain aging.
conferenceObject Human microglia transcriptome and cross-species analysis(2015) GALATRO, T. F. de A.; HOLTMAN, I. R.; BROUWER, N.; SOLA, P.; REIS, G. N.; VAINCHTEIN, I. D.; VERAS, M.; PEREIRA, T.; PASQUALUCCI, C.; SOGAYAR, M. C.; BODDEKE, E. W. G.; MARIE, S. K. N.; EGGEN, B. J. L.- Correlation between molecular features and genetic subtypes of Glioblastoma: critical analysis in 109 cases(2017) GALATRO, Thais F; SOLA, Paula; MORETTI, Isabele F; MIURA, Flavio K; OBA-SHINJO, Sueli M; MARIE, Suely KN; LERARIO, Antonio MOBJECTIVE: Glioblastoma, the most common and lethal brain tumor, is also one of the most defying forms of malignancies in terms of treatment. Integrated genomic analysis has searched deeper into the molecular architecture of GBM, revealing a new sub-classification and promising precision in the care for patients with specific alterations. METHOD: Here, we present the classification of a Brazilian glioblastoma cohort into its main molecular subtypes. Using a high-throughput DNA sequencing procedure, we have classified this cohort into proneural, classical and mesenchymal sub-types. Next, we tested the possible use of the overexpression of the EGFR and CHI3L1 genes, detected through immunohistochemistry, for the identification of the classical and mesenchymal subtypes, respectively. RESULTS: Our results demonstrate that genetic identification of the glioblastoma subtypes is not possible using single targeted mutations alone, particularly in the case of the Mesenchymal subtype. We also show that it is not possible to single out the mesenchymal cases through CHI3L1 expression. CONCLUSION: Our data indicate that the Mesenchymal subtype, the most malignant of the glioblastomas, needs further and more thorough research to be ensure adequate identification.
- GBM Cells Exhibit Susceptibility to Metformin Treatment According to TLR4 Pathway Activation and Metabolic and Antioxidant Status(2023) MORETTI, Isabele Fattori; LERARIO, Antonio Marcondes; SOLA, Paula Rodrigues; MACEDO-DA-SILVA, Janaina; BAPTISTA, Mauricio da Silva; PALMISANO, Giuseppe; OBA-SHINJO, Sueli Mieko; MARIE, Suely Kazue NagahashiSimple Summary An analysis of metformin (MET) treatment in combination with temozolomide (TMZ) in two glioblastoma cell lines, U87MG and A172, stimulated with lipopolysaccharide (LPS), a TLR4 agonist was conducted. Both cells presented blunted mitochondrial respiration leading to oxidative stress after MET treatment, and decreased cell viability after MET + TMZ treatment. U87MG cells presented increased apoptosis after MET + LPS + TMZ treatment by increment of ER stress, and downregulation of BLC2. A172, with an upregulated antioxidant background, including SOD1, exhibited cell cycle arrest after MET + TMZ treatment. The observed differential response was associated with a distinct metabolic status: glycolytic/plurimetabolic (GPM) subtype in U87MG and mitochondrial (MTC) in A172. TCGA-GBM-RNASeq in silico analysis showed that GPM-GBM cases with an activated TLR4 pathway might respond to MET, but the concomitant CXCL8/IL8 upregulation may demand a combination treatment with an IL8 inhibitor. MET combined with an antioxidant inhibitor, such as anti-SOD1, may be indicated for MTC-GBM cases. Glioblastoma (GBM) is an aggressive brain cancer associated with poor overall survival. The metabolic status and tumor microenvironment of GBM cells have been targeted to improve therapeutic strategies. TLR4 is an important innate immune receptor capable of recognizing pathogens and danger-associated molecules. We have previously demonstrated the presence of TLR4 in GBM tumors and the decreased viability of the GBM tumor cell line after lipopolysaccharide (LPS) (TLR4 agonist) stimulation. In the present study, metformin (MET) treatment, used in combination with temozolomide (TMZ) in two GBM cell lines (U87MG and A172) and stimulated with LPS was analyzed. MET is a drug widely used for the treatment of diabetes and has been repurposed for cancer treatment owing to its anti-proliferative and anti-inflammatory actions. The aim of the study was to investigate MET and LPS treatment in two GBM cell lines with different metabolic statuses. MET treatment led to mitochondrial respiration blunting and oxidative stress with superoxide production in both cell lines, more markedly in U87MG cells. Decreased cell viability after MET + TMZ and MET + LPS + TMZ treatment was observed in both cell lines. U87MG cells exhibited apoptosis after MET + LPS + TMZ treatment, promoting increased ER stress, unfolded protein response, and BLC2 downregulation. LPS stimulation of U87MG cells led to upregulation of SOD2 and genes related to the TLR4 signaling pathway, including IL1B and CXCL8. A172 cells attained upregulated antioxidant gene expression, particularly SOD1, TXN and PRDX1-5, while MET treatment led to cell-cycle arrest. In silico analysis of the TCGA-GBM-RNASeq dataset indicated that the glycolytic plurimetabolic (GPM)-GBM subtype had a transcriptomic profile which overlapped with U87MG cells, suggesting GBM cases exhibiting this metabolic background with an activated inflammatory TLR4 pathway may respond to MET treatment. For cases with upregulated CXCL8, coding for IL8 (a pro-angiogenic factor), combination treatment with an IL8 inhibitor may improve tumor growth control. The A172 cell line corresponded to the mitochondrial (MTC)-GBM subtype, where MET plus an antioxidant inhibitor, such as anti-SOD1, may be indicated as a combinatory therapy.
- Integrated transcriptomics uncovers an enhanced association between the prion protein gene expression and vesicle dynamics signatures in glioblastomas(2024) BOCCACINO, Jacqueline Marcia; PEIXOTO, Rafael dos Santos; FERNANDES, Camila Felix de Lima; CANGIANO, Giovanni; SOLA, Paula Rodrigues; COELHO, Barbara Paranhos; PRADO, Mariana Brandao; MELO-ESCOBAR, Maria Isabel; SOUSA, Breno Pereira de; AYYADHURY, Shamini; BADER, Gary D.; SHINJO, Sueli Mieko Oba; MARIE, Suely Kazue Nagahashi; ROCHA, Edroaldo Lummertz da; LOPES, Marilene HohmuthBackgroundGlioblastoma (GBM) is an aggressive brain tumor that exhibits resistance to current treatment, making the identification of novel therapeutic targets essential. In this context, cellular prion protein (PrPC) stands out as a potential candidate for new therapies. Encoded by the PRNP gene, PrPC can present increased expression levels in GBM, impacting cell proliferation, growth, migration, invasion and stemness. Nevertheless, the exact molecular mechanisms through which PRNP/PrPC modulates key aspects of GBM biology remain elusive.MethodsTo elucidate the implications of PRNP/PrPC in the biology of this cancer, we analyzed publicly available RNA sequencing (RNA-seq) data of patient-derived GBMs from four independent studies. First, we ranked samples profiled by bulk RNA-seq as PRNPhigh and PRNPlow and compared their transcriptomic landscape. Then, we analyzed PRNP+ and PRNP- GBM cells profiled by single-cell RNA-seq to further understand the molecular context within which PRNP/PrPC might function in this tumor. We explored an additional proteomics dataset, applying similar comparative approaches, to corroborate our findings.ResultsFunctional profiling revealed that vesicular dynamics signatures are strongly correlated with PRNP/PrPC levels in GBM. We found a panel of 73 genes, enriched in vesicle-related pathways, whose expression levels are increased in PRNPhigh/PRNP+ cells across all RNA-seq datasets. Vesicle-associated genes, ANXA1, RAB31, DSTN and SYPL1, were found to be upregulated in vitro in an in-house collection of patient-derived GBM. Moreover, proteome analysis of patient-derived samples reinforces the findings of enhanced vesicle biogenesis, processing and trafficking in PRNPhigh/PRNP+ GBM cells.ConclusionsTogether, our findings shed light on a novel role for PrPC as a potential modulator of vesicle biology in GBM, which is pivotal for intercellular communication and cancer maintenance. We also introduce GBMdiscovery, a novel user-friendly tool that allows the investigation of specific genes in GBM biology.
- Microglia/macrophages activation status in diffuse gliomas(2016) GALATRO, Thais F.; SOLA, Paula; OBA-SHINJO, Sueli M.; EGGEN, Bart J.; MARIE, Suely K.
- Late p65 nuclear translocation in glioblastoma cells indicates non-canonical TLR4 signaling and activation of DNA repair genes(2021) MORETTI, Isabele F.; LERARIO, Antonio M.; TROMBETTA-LIMA, Marina; SOLA, Paula R.; SOARES, Roseli da Silva; OBA-SHINJO, Sueli M.; MARIE, Suely K. N.Glioblastoma (GBM) is the most aggressive brain primary malignancy. Toll-like receptor 4 (TLR4) has a dual role in cell fate, promoting cell survival or death depending on the context. Here, we analyzed TLR4 expression in different grades of astrocytoma, and observed increased expression in tumors, mainly in GBM, compared to non-neoplastic brain tissue. TLR4 role was investigated in U87MG, a GBM mesenchymal subtype cell line, upon LPS stimulation. p65 nuclear translocation was observed in late phase, suggesting TLR4-non-canonical pathway activation. In fact, components of ripoptosome and inflammasome cascades were upregulated and they were significantly correlated in GBMs of the TCGA-RNASeq dataset. Moreover, an increased apoptotic rate was observed when the GBM-derived U87MG cells were co-treated with LPS and Temozolomide (TMZ) in comparison to TMZ alone. Increased TLR4 immunostaining was detected in nuclei of U87MG cells 12 h after LPS treatment, concomitant to activation of DNA repair genes. Time-dependent increased RAD51, FEN1 and UNG expression levels were confirmed after LPS stimulation, which may contribute to tumor cell fitness. Moreover, the combined treatment with the RAD51 inhibitor, Amuvatinib in combination with, TMZ after LPS stimulation reduced tumor cell viability more than with each treatment alone. In conclusion, our results suggest that stimulation of TLR4 combined with pharmacological inhibition of the DNA repair pathway may be an alternative treatment for GBM patients.