Rhabdoid tumors (RT) are rare and highly aggressive pediatric neoplasms. Their epigenetically-driven intertumoral heterogeneity is well described; however, the cellular origin of RT remains an enigma. Here, we establish and characterize different genetically engineered mouse models driven under the control of distinct promoters and being active in early progenitor cell types with diverse embryonic onsets. From all models only Sox2-positive progenitor cells give rise to murine RT. Using single-cell analyses, we identify distinct cells of origin for the SHH and MYC subgroups of RT, rooting in early stages of embryogenesis. Intra- and extracranial MYC tumors harbor common genetic programs and potentially originate from fetal primordial germ cells (PGCs). Using PGC specific Smarcb1 knockout mouse models we validate that MYC RT originate from these progenitor cells. We uncover an epigenetic imbalance in MYC tumors compared to PGCs being sustained by epigenetically-driven subpopulations. Importantly, treatments with the DNA demethylating agent decitabine successfully impair tumor growth in vitro and in vivo. In summary, our work sheds light on the origin of RT and supports the clinical relevance of DNA methyltransferase inhibitors against this disease.
Background Primary central nervous system lymphoma (PCNSL) is a rare lymphoma of the central nervous system, usually of diffuse large B cell phenotype. Stereotactic biopsy followed by histopathology is the diagnostic standard. However, limited material is available from CNS biopsies, thus impeding an in-depth characterization of PCNSL. Methods We performed flow cytometry, single-cell RNA sequencing, and B cell receptor sequencing of PCNSL cells released from biopsy material, blood, and cerebrospinal fluid (CSF), and spatial transcriptomics of biopsy samples. Results PCNSL-released cells were predominantly activated CD19+CD20+CD38+CD27+ B cells. In single-cell RNA sequencing, PCNSL cells were transcriptionally heterogeneous, forming multiple malignant B cell clusters. Hyperexpanded B cell clones were shared between biopsy- and CSF- but not blood-derived cells. T cells in the tumor microenvironment upregulated immune checkpoint molecules, thereby recognizing immune evasion signals from PCNSL cells. Spatial transcriptomics revealed heterogeneous spatial organization of malignant B cell clusters, mirroring their transcriptional heterogeneity across patients, and pronounced expression of T cell exhaustion markers, co-localizing with a highly malignant B cell cluster. Conclusions Malignant B cells in PCNSL show transcriptional and spatial intratumor heterogeneity. T cell exhaustion is frequent in the PCNSL microenvironment, co-localizes with malignant cells, and highlights the potential of personalized treatments.
Junho de 2013 é um ponto de inflexão para o surgimento acentuado de mobilizações que contribuem para uma ampla reconfiguração do ativismo social. Acreditamos que tal processo implica, por um lado, busca da horizontalidade, autonomia e participação. Por outro lado, a experimentação de outra forma de organização interna, de relações de poder e de tomada de decisões significa conceber, na prática e no quotidiano, um outro “espaço de aparecimento”: tornar visíveis corpos dissidentes, reivindicar a legitimação e o reconhecimento de identidades e culturas historicamente subjugadas. Este artigo propõe analisar o conceito de “coletivos políticos” como sendo aqueles que atuam diretamente com as clivagens sociais. Palavras-chave: Espaço de aparecimento; cultura autonomista; ativismo; coletivos Abstract June 2013 is a turning point for the sharp increase in the mobilizations that contributed to a broad reconfiguration of social activism. This process implies, on the one hand, the search for horizontality, autonomy, and participation. On the other hand, experimenting with another form of internal organization, power relations, and decision-making allows, in practice and daily life, another “space of appearance”: to make dissident bodies visible, claiming legitimation and recognition of historically subjugated identities and cultures. This article proposes to analyze the concept of “political collectives” as those that act directly with social cleavages. Keywords: Space of appearance; autonomism; activism; collective. Resumen Junio de 2013 es un punto clave para el fuerte aumento de las movilizaciones que contribuyen a una amplia reconfiguración del activismo social. Creemos que tal proceso implica, la búsqueda de la horizontalidad, la autonomía y la participación, por un lado. Y, por otro lado, experimentar con otra forma de organización interna, relaciones de poder y toma de decisiones. Lo que significa concebir, en la práctica y en la vida cotidiana, otro “espacio de aparición”: visibilizar los cuerpos disidentes, reivindicar la legitimación y reconocimiento de identidades y culturas históricamente subyugadas. Este artículo propone analizar el concepto de “colectivos políticos” como aquellos que actúan directamente con las asimetrías sociales. Palavras clave: Espacio de aparición; autonomismo; activismo; colectivo.
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