RESUMO
Telomerase-negative tumors maintain telomere length by alternative lengthening of telomeres (ALT), but the underlying mechanism behind ALT remains poorly understood. A proportion of aggressive neuroblastoma (NB), particularly relapsed tumors, are positive for ALT (ALT+), suggesting that a better dissection of the ALT mechanism could lead to novel therapeutic opportunities. TERRA, a long non-coding RNA (lncRNA) derived from telomere ends, localizes to telomeres in a R-loop-dependent manner and plays a crucial role in telomere maintenance. Here we present evidence that RNA modification at the N6 position of internal adenosine (m6A) in TERRA by the methyltransferase METTL3 is essential for telomere maintenance in ALT+ cells, and the loss of TERRA m6A/METTL3 results in telomere damage. We observed that m6A modification is abundant in R-loop enriched TERRA, and the m6A-mediated recruitment of hnRNPA2B1 to TERRA is critical for R-loop formation. Our findings suggest that m6A drives telomere targeting of TERRA via R-loops, and this m6A-mediated R-loop formation could be a widespread mechanism employed by other chromatin-interacting lncRNAs. Furthermore, treatment of ALT+ NB cells with a METTL3 inhibitor resulted in compromised telomere targeting of TERRA and accumulation of DNA damage at telomeres, indicating that METTL3 inhibition may represent a therapeutic approach for ALT+ NB.
Assuntos
Metiltransferases , Neuroblastoma , RNA Longo não Codificante , Humanos , Adenina/análogos & derivados , Metiltransferases/metabolismo , Neuroblastoma/tratamento farmacológico , Neuroblastoma/genética , Neuroblastoma/metabolismo , Estruturas R-Loop , RNA Longo não Codificante/metabolismo , Telômero/genética , Homeostase do TelômeroRESUMO
Background: The vascular heterogeneity of glioblastomas (GB) remains an important area of research, since tumor progression and patient prognosis are closely tied to this feature. With this study, we aim to identify gene expression profiles associated with MRI-defined tumor vascularity and to investigate its relationship with patient prognosis. Methods: The study employed MRI parameters calculated with DSC Perfusion Quantification of ONCOhabitats glioma analysis software and RNA-seq data from the TCGA-GBM project dataset. In our study, we had a total of 147 RNA-seq samples, which 15 of them also had MRI parameter information. We analyzed the gene expression profiles associated with MRI-defined tumor vascularity using differential gene expression analysis and performed Log-rank tests to assess the correlation between the identified genes and patient prognosis. Results: The findings of our research reveal a set of 21 overexpressed genes associated with the high vascularity pattern. Notably, several of these overexpressed genes have been previously implicated in worse prognosis based on existing literature. Our log-rank test further validates that the collective upregulation of these genes is indeed correlated with an unfavorable prognosis. This set of genes includes a variety of molecules, such as cytokines, receptors, ligands, and other molecules with diverse functions. Conclusions: Our findings suggest that the set of 21 overexpressed genes in the High Vascularity group could potentially serve as prognostic markers for GB patients. These results highlight the importance of further investigating the relationship between the molecules such as cytokines or receptors underlying the vascularity in GB and its observation through MRI and developing targeted therapies for this aggressive disease.
RESUMO
Proponemos una visión ampliada de la enfermedad oncológica, fundamentada en un enfoque sistémico de la biología, del estado de salud y de la enfermedad. Tras la revisión previa del microambiente tumoral y la emergencia de nuevos biomarcadores, dedicamos este tercer artículo a la aplicación práctica de esos principios al mundo de la Patología, a través de la identificación, evaluación y análisis cuantitativo de nuevos factores pronósticos y predictivos (Immunoscore, TIME) y el uso clínico de los nuevos y prometedores enfoques de tratamiento oncológico, como la inmunoterapia, mucho más respetuosos con el organismo y que actúan a través de sus propias capacidades de curación. Nace así una propuesta de clasificación y estadificación oncológicas, en manos del patólogo integrador y al servicio de nuevas posibilidades de intervención terapéutica, basadas en la evolución natural del conocimiento científico hacia un campo emergente de aplicación clínica que incluye y a la vez trasciende una concepción puramente genética del cáncer
We propose a comprehensive approach to oncological disease, based on a systemic consideration of biology, health and disease. Our two previous review articles focused on tumour microenvironment and the discovery of new biomarkers; here we discuss the practical application of these principles to pathology, through the identification, evaluation and quantitative analysis of new prognostic and predictive factors (Immunoscore, TIME). We also consider the clinical use of promising, better tolerated treatments, such as immunotherapy. The integrative pathologist now has access to the latest improved oncology stratification tools designed to identify effective treatment strategies, based on the natural evolution of clinical and scientific knowledge that transcend the gene-centric theory of cancer
Assuntos
Humanos , Assistência Integral à Saúde , Biomarcadores Tumorais , Neoplasias/diagnóstico , Neoplasias/terapia , Microambiente Tumoral , Neoplasias/imunologia , Neoplasias/patologia , PrognósticoRESUMO
El grupo de enfermedades al que nos referimos como «cáncer» comparte una estructura biológica conformada por un ecosistema complejo, donde se han alterado las relaciones intercelulares, los campos de información, el desarrollo y la función tisular. Más allá de las alteraciones genéticas de la célula tumoral, la demostración de un ecosistema alterado, con sus interconexiones a nivel sistémico, abre una nueva perspectiva de la biología y del comportamiento del cáncer. Diversas facetas del tumor, su morfología, clasificación, agresividad clínica, pronóstico y respuesta al tratamiento aparecen ahora bajo una visión integral que ofrece un nuevo horizonte de estudio, investigación y manejo clínico. La Teoría de la Mutación Somática en cáncer, vigente desde hace más de 100 años, se ve hoy completada por el estudio del microambiente tumoral, la matriz extracelular, las células estromales, la respuesta inmune, la inervación, la nutrición, la mitocondria, el metabolismo, el fluido intersticial, las propiedades mecánicas y electromagnéticas del tejido, y muchas otras áreas de conocimiento emergente, que abren la puerta a un ejercicio de reprogramación del fenotipo tumoral a través de la modificación de las claves ofrecidas por este nuevo paradigma. Su reconocimiento permite pasar de considerar el proceso oncológico como un problema celular a una alteración supracelular basada en la desorganización de los tejidos, inmersos en las relaciones del sistema complejo que conforma un ser vivo
The group of diseases that we call cancer share a biological structure formed by a complex ecosystem, with altered intercellular communication, information fields, development and tissue function. Beyond the genetic alterations of the tumor cell, the demonstration of an altered ecosystem, with interconnections at systemic levels, opens up a new perspective on cancer biology and behavior. Different tumor facets, such as morphology, classification, clinical aggressiveness, prognosis and response to treatment now appear under a comprehensive vision that offers a new horizon of study, research and clinical management. The Somatic Mutation Theory in cancer, in force for more than one hundred years, is now completed by the study of the tumor microenvironment, the extracellular matrix, the stromal cells, the immune response, the innervation, the nutrition, the mitochondria, the metabolism, the interstitial fluid, the mechanical and electromagnetic properties of the tissue and many other areas of emerging knowledge; thus opening the door to a reprogramming exercise of the tumor phenotype through the modification of the keys offered by this new paradigm. Its recognition makes it possible to go from considering the oncological process as a cellular problem to a supracellular alteration based on the disorganization of tissues, immersed in the relationships of the complex system of the living being
Assuntos
Humanos , Neoplasias/classificação , Gradação de Tumores/métodos , Microambiente Tumoral , Técnicas de Reprogramação Celular/tendências , Matriz Extracelular/patologia , Taxa de MutaçãoRESUMO
El mundo de la Patología cobra sentido de la mano de la Oncología Clínica, donde técnicas y tratamientos, biomarcadores y anticuerpos, comparten el objetivo de hallar nuevas posibilidades de intervención, más eficaces, menos agresivas y más integrales. En esta búsqueda, la evidencia muestra como la mecánica tisular afecta la carcinogénesis y como la heterogeneidad tumoral depende de la alteración metabólica del estroma y del efecto Warburg de las células malignas, regulado directamente por PD-1 y diana del tratamiento inmunoterápico. Proliferación y apoptosis dependen de la disfunción mitocondrial de la célula tumoral que determina el grado de quimio- y radiorresistencia. El estado de la microbiota intestinal determina la respuesta inmune, la estructura del microambiente del tumor y la respuesta al tratamiento oncológico, y el receptor de la vitamina D permite la reprogramación del estroma tumoral. En la actualidad, la colaboración entre los mundos de la investigación básica y clínica establece como zonas de desarrollo próximo el estudio del microambiente tumoral y la mecanoterapia molecular, el metabolismo y la inmunoterapia, la mitocondria y la oncogénesis, la microbiota y la quimioterapia, el eje psiconeuroendocrino y el desequilibrio homeostático, la epigenética y las posibilidades de reprogramación del fenotipo tumoral. De todos estos campos de conocimiento surgen nuevos biomarcadores, pronósticos y predictivos, que revisamos en este artículo al servicio de nuevas posibilidades de intervención terapéutica
Pathology and clinical oncology work hand in hand so that techniques and treatments, biomarkers and antibodies share the common goal of identifying integral new treatment regimens that are more effective and less aggressive. Evidence shows how tissue mechanics affect carcinogenesis and that tumor heterogeneity depends on metabolic stromal alteration and the Warburg effect of malignant cells, regulated directly by PD-1, becoming a target for immunotherapy. Proliferation and apoptosis depend on mitochondrial dysfunction in tumor cells, determining the grade of chemo/radio-resistance. The status of intestinal microbiota regulates immune response, tumor microenvironment structure and oncologic treatment response, whilst the Vitamin D receptor allows reprogramming of tumor stroma. Current collaboration between basic and clinical research paves the way for future investigation into areas such as tumor microenvironment and molecular mechanotherapy, metabolism and immunotherapy, mitochondria and oncogenesis, microbiota and chemotherapy, psychoneuroendocrine axis and homeostatic imbalance, epigenetics and reprogramming possibilities of the tumor phenotype. We review new prognostic and predictive biomarkers emerging from these fields of knowledge, opening up new therapeutic possibilities