Avaliação das respostas ao estresse celular no câncer do sistema nervoso central relacionadas à variação de ploidia

Abstract

Among the most common cancers, central nervous system cancer (CNSC) ranks twelfth, representing an estimated 11,490 new cases annualy in Brazil. Many obstacles hinder successful oncology care for CNSC, including the complex relationship between genomic and chromosomal instability in driving tumor resistance and metastasis. In this context, this study investigated how ploidy variation affects tumor response, particularly in gliomas, with a focus on polyploid/multinucleated giant cancer cels (PGCCs/MNGCs). The main objective was to elucidate therapeutic stress mechanisms that promote tumor plasticity and to identify potential prognostic biomarkers through an integrated approach combining computational biology and translational studies with digital pathology. This approach included in silico analyses of protein-protein interaction networks using tools like STRING and Cytoscape (performing topological and functional evaluations via MCODE, stringApp, and Cytohubba), in vitro assays with U87 cells treated with temozolomide (conducted through single-ce l tracking and microscopic image analyses), and a translational study of histological samples from CNS tumor patients at the Central State Hospital/iNOVACapixaba, analyzed using the QuPath program. The results highlighted key biomarkers identified through signaling pathways such as EGFR/RAS/MAPK, PI3K/mTOR, and STAT3, supporting the metabolic resilience and invasiveness of PGCCs/MNGCs. Additionaly, IDH mutations, lipid metabolism alterations, aerobic glycolysis, autophagy, proteins such as cofilin, fascin-1, and tropomyosins, genomic instability, and ABC transporters were shown to impact chemoresistance and tumor progression. Histomorphometric analysis revealed the distribution of giant nuclei ce ls 11 across different tumor subtypes, with a predominance in Metastasis/Invasion (31%), Grade I Meningioma (28%), and Schwannoma (27%). A lower prevalence of giant nuclei was observed in tumors such as Grade II Ependymoma (7%) and GB/Grade IV Astrocytoma (3%), reinforcing the morphological heterogeneity described in the literature. Statistical analysis indicated normality in area values (p=0.759) and homogeneity of variances (p=0.367), while ANOVA testing revealed significant differences in area among tumor groups (p=0.032), notably between GB/Grade IV Astrocytoma and Metastasis/Invasion, validated by the Tukey HSD test (p=0.017). Schwannoma displayed high variability in nuclear area (CV=12.92%), indicating structural diversity. These findings confirmed potential correlations between ploidy variation and tumor progression, identifying them as potential prognostic biomarkers or tools for more precise prognostic assessments. It was concluded that integrating computational, laboratory, and histological analyses allows significant advancements in personalized antitumor therapies, emphasizing the importance of adaptive strategies in managing CNSC, especialy gliomas. This work contributes significantly to biotechnology and opens new therapeutic avenues based on PGCCs/MNGCs dynamics. Additiona ly, it marked a professional advancement with diverse outputs, including publications (71 in total), technical and extension contributions (4 courses taught), events (7, including 3 international ones—Spain, NASA/USA, Houston/USA), and a technical-scientific internship (Portugal, funded by FAPES)