RESUMO
A subset of patients with IDH-mutant glioma respond to inhibitors of mutant IDH (IDHi), yet the molecular underpinnings of such responses are not understood. Here, we profiled by single-cell or single-nucleus RNA-sequencing three IDH-mutant oligodendrogliomas from patients who derived clinical benefit from IDHi. Importantly, the tissues were sampled on-drug, four weeks from treatment initiation. We further integrate our findings with analysis of single-cell and bulk transcriptomes from independent cohorts and experimental models. We find that IDHi treatment induces a robust differentiation toward the astrocytic lineage, accompanied by a depletion of stem-like cells and a reduction of cell proliferation. Furthermore, mutations in NOTCH1 are associated with decreased astrocytic differentiation and may limit the response to IDHi. Our study highlights the differentiating potential of IDHi on the cellular hierarchies that drive oligodendrogliomas and suggests a genetic modifier that may improve patient stratification.
Assuntos
Neoplasias Encefálicas , Diferenciação Celular , Isocitrato Desidrogenase , Mutação , Oligodendroglioma , Oligodendroglioma/genética , Oligodendroglioma/patologia , Oligodendroglioma/tratamento farmacológico , Isocitrato Desidrogenase/genética , Isocitrato Desidrogenase/antagonistas & inibidores , Humanos , Diferenciação Celular/efeitos dos fármacos , Neoplasias Encefálicas/genética , Neoplasias Encefálicas/patologia , Neoplasias Encefálicas/tratamento farmacológico , Linhagem da Célula/efeitos dos fármacos , Receptor Notch1/genética , Receptor Notch1/metabolismo , Proliferação de Células/efeitos dos fármacos , Animais , Astrócitos/metabolismo , Astrócitos/efeitos dos fármacos , Astrócitos/patologia , Camundongos , Análise de Célula Única/métodosRESUMO
Diffusely infiltrating gliomas - including glioblastoma (GBM), isocitrate dehydrogenase (IDH) mutant gliomas, and histone 3 (H3) altered gliomas - are primary brain tumors with an invariably fatal outcome. Despite advances in the understanding of their biology, standard, targeted and immune checkpoint inhibitor immunotherapies have proven ineffective in arresting their inexorable progression and associated morbidity and mortality. Recognizing the unique aspects of the immunogenicity of cancer cells, the last decade has seen the development and evaluation of vaccine-based therapies for the treatment of solid tumors, including gliomas. Here we review the current vaccine strategies for the treatment of GBM, IDH-mutant gliomas and diffuse midline glioma H3 K27M-altered. We discuss potential benefits and challenges of vaccine therapies in these specific patient populations.
RESUMO
Glioblastoma, the most malignant brain tumor in adults, exhibits characteristic patterns of epigenetic alterations that await elucidation. The DNA methylome of glioblastoma revealed recurrent epigenetic silencing of HTATIP2, which encodes a negative regulator of importin ß-mediated cytoplasmic-nuclear protein translocation. Its deregulation may thus alter the functionality of cancer-relevant nuclear proteins, such as the base excision repair (BER) enzyme N-methylpurine DNA glycosylase (MPG), which has been associated with treatment resistance in GBM. We found that induction of HTATIP2 expression in GBM cells leads to a significant shift of predominantly nuclear to cytoplasmic MPG, whereas depletion of endogenous HTATIP2 results in enhanced nuclear MPG localization. Reduced nuclear MPG localization, prompted by HTATIP2 expression or by depletion of MPG, yielded less phosphorylated-H2AX-positive cells upon treatment with an alkylating agent. This suggested reduced MPG-mediated formation of apurinic/apyrimidinic sites, leaving behind unrepaired DNA lesions, reflecting a reduced capacity of BER in response to the alkylating agent. Epigenetic silencing of HTATIP2 may thus increase nuclear localization of MPG, thereby enhancing the capacity of the glioblastoma cells to repair treatment-related lesions and contributing to treatment resistance.
Assuntos
DNA Glicosilases , Glioblastoma , Humanos , Glioblastoma/tratamento farmacológico , Glioblastoma/genética , Glioblastoma/patologia , Reparo do DNA/genética , DNA Glicosilases/genética , Alquilantes , Proteínas Nucleares/genética , Epigênese Genética , Acetiltransferases/genética , Acetiltransferases/metabolismo , Fatores de Transcrição/metabolismoRESUMO
Medical students from the University of Lausanne volunteered rapidly and in great number to bolster health facilities across Switzerland in response to the COVID-19 pandemic. At Unisanté, Center for general practice and public health, University of Lausanne, students recruited as interns discovered the different aspects of primary care. This extraordinary period naturally involves considerable challenges but represents also a precious learning opportunity for future doctors.
Les étudiants en médecine de l'Université de Lausanne se sont rapidement et massivement portés volontaires pour soutenir les institutions de soins en Suisse face à la pandémie du Covid-19. À Unisanté, Centre universitaire de médecine générale et santé publique de Lausanne, les étudiants engagés comme médecins stagiaires ont pu découvrir les différentes facettes de la médecine de premier recours. Cette situation extraordinaire comporte naturellement ses défis, mais représente également une opportunité précieuse d'apprentissage pour les futurs médecins.
