Biology subjects

Thomaz, A.

Publications and source records attributed to Thomaz, A..

5 recordsLinked to original sources

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↗

bioRxiv2026

Subgroup-Specific Associations of GRIA Genes Encoding AMPA Glutamate Receptor Subunits with Patient Survival in Medulloblastoma

Brain cancers hijack biological systems involved in neural development and synaptic plasticity. Medulloblastoma (MB), the most common malignant brain tumor in children, is thought to arise from disruptions in neurodevelopmental programs. Glutamatergic transmission mediated by -amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptors (AMPARs) has been implicated in synaptic communication between adult brain tumors and surrounding neurons; however, the possible role of AMPARs in MB remains largely unexplored. Here, we analyzed the expression of genes encoding AMPAR subunits, GRIA1-4, in datasets of MB tumor and cell lines, revealing distinct expression patterns and associations with overall survival (OS) across molecular subgroups and histological variants. Expression levels differed among MB molecular subgroups. Analysis using single-cell RNA sequencing (scRNA-seq) was consistent with enrichment of GRIA1 in Group 3 and GRIA4 in SHH MB. Higher GRIA1, GRIA2, and GRIA4 transcription was associated with more favorable patient outcomes in specific MB subgroups. In contrast, high expression of GRIA3 in SHH, or of either GRIA3 or GRIA4 in Group 3 MB, was associated with worse prognosis. Particularly robust but opposing associations with patient survival were found for GRIA3 and GRIA4 in SHH MB. Analysis of GRIA mRNA levels in MB cell lines using both quantitative reverse transcription polymerase chain reaction (qRT-PCR) and data from The Human Protein Atlas, supported some of the gene expression patterns observed in tumors. Together, these findings suggest that GRIA genes and their corresponding AMPAR subunits may have subgroup-specific prognostic relevance in MB.

cancer biology↗

bioRxiv2025

Moonlighting Role of Meiotic SYCP1 in Breast Cancer: A Chromatin-Bound Regulator of DNA Repair, Transcription, and Drug Resistance

Maintenance of genome integrity is essential for cellular homeostasis, and its perturbation leads to tumorigenesis. Here, we uncover an unanticipated somatic role for the synaptonemal complex protein SYCP1--previously regarded as strictly meiosis-specific--in a broad spectrum of human cancers including breast cancer. Through integrative genomic, proteomic, and functional analyses, we demonstrate that SYCP1 is aberrantly re-expressed in tumor cells, where it actively promotes DNA damage repair, cell cycle progression, and malignant growth. SYCP1 binds chromatin at regulatory elements and directly controls transcriptional programs governing genome maintenance, including key effectors such as CCNB1, PCNA, RAD51C, and H2AX. Loss of SYCP1 impairs DNA repair kinetics, attenuates tumor cell proliferation and migration, and increases sensitivity to chemotherapeutics cisplatin and gemcitabine. Mechanistically, SYCP1 interfaces with chromatin remodeling complexes and transcription factors SP1 and SP2, modulating their genomic occupancy and facilitating oncogenic transcriptional outputs. Clinically, high SYCP1 expression stratifies patients with poor prognosis and therapy resistance across multiple cancer types. Our findings illuminate a previously unrecognized moonlighting function of SYCP1 in somatic cancer cells and position it as a critical chromatin-associated regulator of genome stability, with implications for biomarker development and therapeutic targeting.

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↗