Biology subjects

de Farias, C. B.

Publications and source records attributed to de Farias, C. B..

9 recordsLinked to original sources

bioRxiv2026

The neuronal plasticity gene CRTC1 links survival with mitochondrial programs and tumor microenvironment features in Group 3 β medulloblastoma

CREB-regulated transcription coactivator 1 (CRTC1) regulates neuronal development, plasticity, and activity-dependent transcription, but its role in medulloblastoma (MB) remains poorly understood. We investigated expression of the CRTC1 gene during human cerebellar development and across pediatric brain tumors and examined its molecular and clinical associations in MB using public transcriptomic datasets. CRTC1 was broadly expressed in the developing cerebellum, with cell-state-specific variation within the granule-cell lineage. Among pediatric brain tumors, MB showed the highest median CRTC1 expression, which differed significantly among MB molecular groups and subtypes, with highest levels in Group 4 MB. High CRTC1 expression was associated with longer overall survival specifically in Group 3 {beta} MB and remained significant after correction across the 12 molecular subtypes. Within Group 3 {beta} tumors, CRTC1 expression was inversely associated with enrichment of mitochondrial and bioenergetic processes, including oxidative phosphorylation, mitochondrial organization, and mitochondrial translation, whereas CRTC1-high and CRTC1-low tumors displayed distinct transcriptional profiles. CRTC1 was also associated with selected cell-type-related transcriptional signatures related to the tumor microenvironment. These findings identify CRTC1 as a marker of biologically and clinically relevant transcriptional heterogeneity in Group 3 {beta} MB and support further investigation of its functional and prognostic significance.

cancer biology↗

bioRxiv2026

PSEN1 Expression Identifies a Developmentally Distinct Favorable-Prognosis State in SHH α Medulloblastoma

Background: Although PSEN1 is best known for its role in Alzheimer's disease, it also regulates neural development and cerebellar morphogenesis. Medulloblastoma (MB) is the most common malignant pediatric brain tumor and arises from disrupted cerebellar developmental programs. The clinical significance of PSEN1 in MB remains unknown. We investigated the prognostic value and transcriptional correlates of PSEN1 expression across molecular subgroups and subtypes of MB. Methods: Public bulk and single-cell transcriptomic datasets were used to examine PSEN1 expression, associations with overall survival (OS), and transcriptional correlates in MB. The SHH -associated transcriptional pattern was evaluated in an independent cohort, and PSEN1 expression was further examined in the developing human cerebellum and across pediatric brain tumor types. Genes strongly correlated with PSEN1 in SHH MB were subjected to Gene Ontology (GO) enrichment analysis. Results: High PSEN1 expression was consistently associated with significantly longer OS exclusively in SHH MB. The PSEN1-associated transcriptional pattern was reproduced in an independent SHH cohort. PSEN1 was expressed across developing cerebellar cell populations and pediatric brain tumor types, with MB showing intermediate expression among the tumor entities examined. In SHH MB, PSEN1 was associated with a coordinated transcriptional program enriched for RNA homeostasis, intracellular membrane trafficking, protein quality control, lipid and calcium signaling, and developmental pathways. Conclusions: High PSEN1 expression identifies a favorable-prognosis subset of SHH MB and is associated with a distinct transcriptional program related to endomembrane organization and cellular homeostasis rather than canonical SHH signaling. These findings suggest that PSEN1 may mark a developmentally distinct tumor state and generate new hypotheses regarding subtype-specific developmental programs in MB.

cancer biology↗

bioRxiv2025

Delayed growth of Ewing sarcoma tumors associated with reduced expression and activity of Trk receptors, PI3K, and IGF1R

Ewing sarcoma (ES) is an aggressive childhood tumor. We have previously shown that tropomyosin receptor kinase (Trk) neurotrophin receptors regulate viability, and the pan-Trk and kinase inhibitor K252a restores sensitivity to chemotherapy, in ES cells. Here, we show that administration of K252a in mice delays ES tumor growth and reduces expression and activity of multiple targets. BALB/c nu/nu nude mice inoculated with SK-ES-1 ES cells were given daily intraperitoneal (i.p.) injections of K252a for 18 days. Immunohistochemical analysis of tumors was performed to quantify the expression and phosphorylation of Trk receptors, phosphoinositide 3-kinase (PI3K), and insulin-like growth factor 1 receptor (IGF1R). Associations between genes encoding Trks, PI3G, and IGF1R and overall survival (OS) in patients with ES was examined. Treatment with K252a led to a transient delay in ES tumor growth and reduced the expression and phosphorylation of TrkA, TrkB, PI3K, and IGF1R. Combined treatment with K252a and the IGF1R inhibitor NVP-ADW742 was more effective in reducing ES cell viability than each compound alone. Significant associations between expression of NTRK genes and patient OS were found, indicating that NTRK genes should be further evaluated as biomarkers for prognosis in patients with ES.

cancer biology↗

bioRxiv2024

Modulation of Stemness and Differentiation Regulators by Valproic Acid in Medulloblastoma

Changes in epigenetic processes such as histone acetylation are proposed as key events influencing cancer cell function and the initiation and progression of pediatric brain tumors. Valproic acid (VPA) is an antiepileptic drug that acts partially by inhibiting histone deacetylases (HDACs) and could be repurposed as an epigenetic anticancer therapy. Here, we show that VPA reduced medulloblastoma (MB) cell viability and led to cell cycle arrest. These effects were accompanied by enhanced H3K9 histone acetylation (H3K9ac) and decreased expression of the MYC oncogene. VPA impaired the expansion of MB neurospheres enriched in stemness markers and reduced MYC while increasing TP53 expression in these neurospheres. In addition, VPA induced morphological changes consistent with neuronal differentiation and the increased expression of differentiation marker genes TUBB3 and ENO2. The expression of stemness genes SOX2, NES, and PRTG was differentially affected by VPA in MB cells with different TP53 status. VPA increased H3K9 occupancy of the promoter region of TP53. Among the genes regulated by VPA, the stemness regulators MYC and NES showed an association with patient survival in specific MB subgroups. Our results indicate that VPA may exert antitumor effects in MB by influencing histone acetylation, which may result in the modulation of stemness, neuronal differentiation, and the expression of genes associated with patient prognosis in specific molecular subgroups. Importantly, the actions of VPA in MB cells and neurospheres include a reduction in the expression of MYC and an increase in TP53.

cancer biology↗

bioRxiv2023

Modulation of Viability, Proliferation, and Stemness by Rosmarinic Acid in Medulloblastoma Cells: Involvement of HDACs and EGFR

Medulloblastoma (MB) is a heterogeneous group of malignant pediatric brain tumors, divided into molecular groups with distinct biological features and prognosis. Currently available therapy often results in poor long-term quality of life for patients, which will be afflicted by neurological, neuropsychiatric, and emotional sequelae. Identifying novel therapeutic agents capable of targeting the tumors without jeopardizing patients quality of life is imperative. Rosmarinic acid (RA) is a plant-derived compound whose action against a series of diseases including cancer has been investigated, with no side effects reported so far. Previous studies have not examined whether RA has effects in MB. Here, we show RA is cytotoxic against human Daoy (IC50= 168 M) and D283 (IC50= 334 M) MB cells. Exposure to RA for 48 h reduced histone deacetylase 1 (HDAC1) expression while increasing H3K9 hyperacetylation, reduced epidermal growth factor (EGFR) expression, and inhibited EGFR downstream targets extracellular-regulated kinase (ERK)1/2 and AKT in Daoy cells. These modifications were accompanied by increased expression of CDKN1A/p21, reduced expression of SOX2, and a decrease in proliferative rate. Treatment with RA also reduced cancer stem cell markers expression and neurosphere size. Taken together, our findings indicate that RA can reduce cell proliferation and stemness and induce cell cycle arrest in MB cells. Mechanisms mediating these effects may include targeting HDAC1, EGFR, and ERK signaling, and promoting p21 expression, possibly through an increase in H3K9ac and AKT deactivation. RA should be further investigated as a potential anticancer agent in experimental MB.

cancer biology↗

bioRxiv2020

Expression and Pharmacological Inhibition of TrkB and EGFR in Glioblastoma

Background A member of the Trk family of neurotrophin receptors, tropomyosin receptor kinase B (TrkB, encoded by the NTRK2 gene) is an increasingly important target in various cancer types, including glioblastoma (GBM). EGFR is among the most frequently altered oncogenes in GBM, and EGFR inhibition has been tested as an experimental therapy. Functional interactions between EGFR and TrkB have been demonstrated. In the present study, we investigated the role of TrkB and EGFR, and their interactions, in GBM.Methods and Results Analyses of NTRK2 and EGFR gene expression from The Cancer Genome Atlas (TCGA) datasets showed an increase in NTRK2 expression in the proneural subtype of GBM, and a strong correlation between NTRK2 and EGFR expression in glioma CpG island methylator phenotype (G-CIMP+) samples. We showed that when TrkB and EGFR inhibitors were combined, the inhibitory effect on A172 human GBM cells was more pronounced than when either inhibitor was given alone. When U87MG GBM cells were xenografted into the flank of nude mice, tumor growth was delayed by treatment with TrkB and EGFR inhibitors, given alone or combined, only at specific time points. Intracranial GBM growth in mice was not significantly affected by drug treatments.Conclusions Our findings indicate that correlations between NTRK2 and EGFR expression occur in specific GBM subgroups. Also, our results using cultured cells suggest for the first time the potential of combining TrkB and EGFR inhibition for the treatment of GBM.Competing Interest StatementThe authors have declared no competing interest.View Full Text

cancer biology↗

bioRxiv2019

Antitumor Activities and Cellular Changes Induced by TrkB Inhibition in Medulloblastoma

Neurotrophins are critically involved in regulating in normal neural development and plasticity. Brain-derived neurotrophic factor (BDNF), a neurotrophin that acts by binding to the tropomyosin receptor kinase B (TrkB) receptor, has also been implicated in the progression of several types of cancer. However, its role in medulloblastoma (MB), the most common type of malignant brain tumor afflicting children, remains unclear. Here we show that selective TrkB inhibition with the small molecule compound ANA-12 impaired proliferation and viability of human UW228 and D283 MB cells. These effects were accompanied by increased apoptosis, reduced extracellular-regulated kinase (ERK) activity, increased expression of signal transducer and activator of transcription 3 (STAT3), and differential modulation of p21 expression dependent on the cell line. In addition, MB cells treated with ANA-12 showed morphological alterations consistent with differentiation, increased levels of the neural differentiation marker {beta}-III Tubulin (TUBB3), and reduced expression of the stemness marker Nestin. Finally, TrkB inhibition was able to slow the growth of MB tumors xenografted into nude mice. These findings are consistent with the hypothesis that selective TrkB inhibition can display consistent anticancer effects in MB, possibly by modulating intracellular signaling and gene expression related to tumor progression, apoptosis, and differentiation.

cancer biology↗

bioRxiv2019

HDAC and MAPK/ERK Inhibitors Cooperate to Reduce Viability and Stemness Phenotype in Medulloblastoma

Medulloblastoma (MB), which originates from embryonic neural stem cells (NSCs) or neural precursors in the developing cerebellum, is the most common malignant brain tumor of childhood. Recurrent and metastatic disease is the principal cause of death and may be related to resistance within cancer stem cells (CSCs). Chromatin state is involved in maintaining signaling pathways related to stemness, and inhibition of histone deacetylase enzymes (HDAC) has emerged as an experimental therapeutic strategy to target this cell population. Here, we observed antitumor actions and changes in stemness induced by HDAC inhibition in MB. Analyses of tumor samples from patients with MB showed that the stemness markers BMI1 and CD133 are expressed in all molecular subgroups of MB. The HDAC inhibitor (HDACi) NaB reduced cell viability and expression of BMI1 and CD133 and increased acetylation in human MB cells. Enrichment analysis of genes associated with CD133 or BMI1 expression showed mitogen-activated protein kinase (MAPK)/ERK signaling as the most enriched processes in MB tumors. MAPK/ERK inhibition reduced expression of the stemness markers, hindered MB neurosphere formation, and its antiproliferative effect was enhanced by combination with NaB. These results suggest that combining HDAC and MAPK/ERK inhibitors may be a novel and more effective approach in reducing MB proliferation when compared to single-drug treatments, through modulation of the stemness phenotype of MB cells.

cancer biology↗

bioRxiv2017

Targeting histone deacetylase activity to arrest cell growth and promote neural differentiation in Ewing sarcoma

There is an urgent need for advances in the treatment of Ewing sarcoma (EWS), an aggressive childhood tumor with possible neuroectodermal origin. Inhibition of histone deacetylases (HDAC) can revert aberrant epigenetic states and reduce growth in different experimental cancer types. Here, we investigated whether the potent HDAC inhibitor, sodium butyrate (NaB) has the ability to reprogram EWS cells towards a more differentiated state and affect their growth and survival. Exposure of two EWS cell lines to NaB resulted in rapid and potent inhibition of HDAC activity (1 h, IC50 1.5 mM) and a significant arrest of cell cycle progression (72 h, IC50 0.68-0.76 mM), marked by G0/G1 accumulation. Delayed cell proliferation and reduced colony formation ability were observed in EWS cells after long-term culture. NaB-induced effects included suppression of cell proliferation accompanied by reduced transcriptional expression of the EWS-FLI1 fusion oncogene, decreased expression of key survival and pluripotency-associated genes, and re-expression of the differentiation neuronal marker {superscript 2}III-tubulin. Finally, NaB reduced c-MYC levels and impaired survival in putative EWS cancer stem cells. Our findings support the use of HDAC inhibition as a strategy to impair cell growth and survival and to reprogram EWS tumors towards differentiation. These results are consistent with our previous studies indicating that HDis can inhibit the growth and modulate differentiation of cells from other types of childhood pediatric tumors possibly originating from neural stem cells.

cancer biology↗