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1.
Semin Cancer Biol ; 61: 30-41, 2020 04.
Artigo em Inglês | MEDLINE | ID: mdl-31923457

RESUMO

Malignant Rhabdoid Tumours (MRT) are the quintessential example of an epigenetic cancer. Mutation of a single gene, SMARCB1 or more rarely SMARCA4, is capable of causing one of the most aggressive and lethal cancers of early childhood and infancy. SMARCB1 encodes a core subunit of the SWI/SNF complex and its mutation evokes genome-wide downstream effects which may be counteracted therapeutically. Here we review and discuss the use of translational genomics in the study of MRT biology and the ways in which this has impacted clinical practice or may do so in the future. First, the diagnosis and definition of MRT and the transition from a histopathological to a molecular definition. Second, epigenetic and transcriptomic subgroups within MRT, their defining features and potential prognostic or therapeutic significance. Third, functional genomic studies of MRT by mouse modelling and forced re-expression of SMARCB1 in MRT cells. Fourth, studies of underlying epigenetic mechanisms (e.g. EZH2, HDACs) or deregulated kinases (e.g. PDGFR, FGFR1) and the potential therapeutic opportunities these provide. Finally, we discuss likely future directions and proffer opinion on how future translational genomics should be integrated into future biological/clinical studies to select and evaluate the best anti-MRT therapeutic agents.


Assuntos
Transformação Celular Neoplásica/genética , Predisposição Genética para Doença , Genômica , Tumor Rabdoide/genética , Pesquisa Translacional Biomédica , Animais , Transformação Celular Neoplásica/metabolismo , DNA Helicases/genética , Epigênese Genética , Perfilação da Expressão Gênica , Estudos de Associação Genética , Heterogeneidade Genética , Genômica/métodos , Genótipo , Humanos , Camundongos , Mutação , Proteínas Nucleares/genética , Fenótipo , Tumor Rabdoide/diagnóstico , Tumor Rabdoide/metabolismo , Fatores de Transcrição/genética
2.
Sci Adv ; 10(10): eadl0515, 2024 Mar 08.
Artigo em Inglês | MEDLINE | ID: mdl-38446884

RESUMO

Single-cell RNA sequencing has revolutionized our understanding of cellular heterogeneity, but routine methods require cell lysis and fail to probe the dynamic trajectories responsible for cellular state transitions, which can only be inferred. Here, we present a nanobiopsy platform that enables the injection of exogenous molecules and multigenerational longitudinal cytoplasmic sampling from a single cell and its progeny. The technique is based on scanning ion conductance microscopy (SICM) and, as a proof of concept, was applied to longitudinally profile the transcriptome of single glioblastoma (GBM) brain tumor cells in vitro over 72 hours. The GBM cells were biopsied before and after exposure to chemotherapy and radiotherapy, and our results suggest that treatment either induces or selects for more transcriptionally stable cells. We envision the nanobiopsy will contribute to transforming standard single-cell transcriptomics from a static analysis into a dynamic assay.


Assuntos
Perfilação da Expressão Gênica , Glioblastoma , Humanos , Citoplasma , Transcriptoma , Citosol , Bioensaio , Glioblastoma/genética
3.
Neuro Oncol ; 25(7): 1236-1248, 2023 07 06.
Artigo em Inglês | MEDLINE | ID: mdl-36689332

RESUMO

BACKGROUND: Characterizing and quantifying cell types within glioblastoma (GBM) tumors at scale will facilitate a better understanding of the association between the cellular landscape and tumor phenotypes or clinical correlates. We aimed to develop a tool that deconvolutes immune and neoplastic cells within the GBM tumor microenvironment from bulk RNA sequencing data. METHODS: We developed an IDH wild-type (IDHwt) GBM-specific single immune cell reference consisting of B cells, T-cells, NK-cells, microglia, tumor associated macrophages, monocytes, mast and DC cells. We used this alongside an existing neoplastic single cell-type reference for astrocyte-like, oligodendrocyte- and neuronal progenitor-like and mesenchymal GBM cancer cells to create both marker and gene signature matrix-based deconvolution tools. We applied single-cell resolution imaging mass cytometry (IMC) to ten IDHwt GBM samples, five paired primary and recurrent tumors, to determine which deconvolution approach performed best. RESULTS: Marker-based deconvolution using GBM-tissue specific markers was most accurate for both immune cells and cancer cells, so we packaged this approach as GBMdeconvoluteR. We applied GBMdeconvoluteR to bulk GBM RNAseq data from The Cancer Genome Atlas and recapitulated recent findings from multi-omics single cell studies with regards associations between mesenchymal GBM cancer cells and both lymphoid and myeloid cells. Furthermore, we expanded upon this to show that these associations are stronger in patients with worse prognosis. CONCLUSIONS: GBMdeconvoluteR accurately quantifies immune and neoplastic cell proportions in IDHwt GBM bulk RNA sequencing data and is accessible here: https://gbmdeconvoluter.leeds.ac.uk.


Assuntos
Neoplasias Encefálicas , Glioblastoma , Humanos , Glioblastoma/patologia , Transcriptoma , Neoplasias Encefálicas/patologia , Perfilação da Expressão Gênica/métodos , Microglia/metabolismo , Microambiente Tumoral
4.
Nat Med ; 26(5): 712-719, 2020 05.
Artigo em Inglês | MEDLINE | ID: mdl-32341579

RESUMO

Atypical teratoid/rhabdoid tumors (ATRTs) typically arise in the central nervous system (CNS) of children under 3 years of age. Despite intensive multimodal therapy (surgery, chemotherapy and, if age permits, radiotherapy), median survival is 17 months1,2. We show that ATRTs robustly express B7-H3/CD276 that does not result from the inactivating mutations in SMARCB1 (refs. 3,4), which drive oncogenesis in ATRT, but requires residual SWItch/Sucrose Non-Fermentable (SWI/SNF) activity mediated by BRG1/SMARCA4. Consistent with the embryonic origin of ATRT5,6, B7-H3 is highly expressed on the prenatal, but not postnatal, brain. B7-H3.BB.z-chimeric antigen receptor (CAR) T cells administered intracerebroventricularly or intratumorally mediate potent antitumor effects against cerebral ATRT xenografts in mice, with faster kinetics, greater potency and reduced systemic levels of inflammatory cytokines compared to CAR T cells administered intravenously. CAR T cells administered ICV also traffic from the CNS into the periphery; following clearance of ATRT xenografts, B7-H3.BB.z-CAR T cells administered intracerebroventricularly or intravenously mediate antigen-specific protection from tumor rechallenge, both in the brain and periphery. These results identify B7-H3 as a compelling therapeutic target for this largely incurable pediatric tumor and demonstrate important advantages of locoregional compared to systemic delivery of CAR T cells for the treatment of CNS malignancies.


Assuntos
Antígenos B7/imunologia , Neoplasias Encefálicas/terapia , Vacinas Anticâncer/administração & dosagem , Imunoterapia Adotiva/métodos , Tumor Rabdoide/terapia , Teratoma/terapia , Adulto , Animais , Encéfalo/efeitos dos fármacos , Encéfalo/imunologia , Encéfalo/patologia , Neoplasias Encefálicas/imunologia , Neoplasias Encefálicas/patologia , Células Cultivadas , Pré-Escolar , Feminino , Feto/patologia , Humanos , Lactente , Injeções Intraventriculares , Camundongos , Camundongos Endogâmicos NOD , Camundongos SCID , Receptores de Antígenos Quiméricos/administração & dosagem , Receptores de Antígenos Quiméricos/genética , Receptores de Antígenos Quiméricos/imunologia , Tumor Rabdoide/imunologia , Tumor Rabdoide/patologia , Linfócitos T/imunologia , Linfócitos T/metabolismo , Linfócitos T/transplante , Teratoma/imunologia , Teratoma/patologia , Ensaios Antitumorais Modelo de Xenoenxerto
5.
Cancer Cell ; 35(1): 95-110.e8, 2019 01 14.
Artigo em Inglês | MEDLINE | ID: mdl-30595504

RESUMO

Biallelic inactivation of SMARCB1, encoding a member of the SWI/SNF chromatin remodeling complex, is the hallmark genetic aberration of atypical teratoid rhabdoid tumors (ATRT). Here, we report how loss of SMARCB1 affects the epigenome in these tumors. Using chromatin immunoprecipitation sequencing (ChIP-seq) on primary tumors for a series of active and repressive histone marks, we identified the chromatin states differentially represented in ATRTs compared with other brain tumors and non-neoplastic brain. Re-expression of SMARCB1 in ATRT cell lines enabled confirmation of our genome-wide findings for the chromatin states. Additional generation of ChIP-seq data for SWI/SNF and Polycomb group proteins and the transcriptional repressor protein REST determined differential dependencies of SWI/SNF and Polycomb complexes in regulation of diverse gene sets in ATRTs.


Assuntos
Cromatina/metabolismo , Proteínas do Grupo Polycomb/metabolismo , Proteínas Repressoras/metabolismo , Tumor Rabdoide/metabolismo , Proteína SMARCB1/metabolismo , Teratoma/metabolismo , Sítios de Ligação , Encéfalo/metabolismo , Linhagem Celular Tumoral , Imunoprecipitação da Cromatina , Epigenômica/métodos , Regulação Neoplásica da Expressão Gênica , Histonas/metabolismo , Humanos , Proteína SMARCB1/química , Análise de Sequência de DNA , Análise de Sobrevida
6.
Cell Rep ; 17(5): 1265-1275, 2016 10 25.
Artigo em Inglês | MEDLINE | ID: mdl-27783942

RESUMO

Subunits of the SWI/SNF chromatin remodeling complex are mutated in a significant proportion of human cancers. Malignant rhabdoid tumors (MRTs) are lethal pediatric cancers characterized by a deficiency in the SWI/SNF subunit SMARCB1. Here, we employ an integrated molecular profiling and chemical biology approach to demonstrate that the receptor tyrosine kinases (RTKs) PDGFRα and FGFR1 are coactivated in MRT cells and that dual blockade of these receptors has synergistic efficacy. Inhibitor combinations targeting both receptors and the dual inhibitor ponatinib suppress the AKT and ERK1/2 pathways leading to apoptosis. MRT cells that have acquired resistance to the PDGFRα inhibitor pazopanib are susceptible to FGFR inhibitors. We show that PDGFRα levels are regulated by SMARCB1 expression, and assessment of clinical specimens documents the expression of both PDGFRα and FGFR1 in rhabdoid tumor patients. Our findings support a therapeutic approach in cancers with SWI/SNF deficiencies by exploiting RTK coactivation dependencies.


Assuntos
Receptor Tipo 1 de Fator de Crescimento de Fibroblastos/antagonistas & inibidores , Receptor alfa de Fator de Crescimento Derivado de Plaquetas/antagonistas & inibidores , Tumor Rabdoide/metabolismo , Tumor Rabdoide/patologia , Apoptose/efeitos dos fármacos , Linhagem Celular Tumoral , Dasatinibe/farmacologia , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Perfilação da Expressão Gênica , Humanos , Indazóis , Indóis/farmacologia , Oncogenes , Pirimidinas/farmacologia , Pirróis/farmacologia , Receptor Tipo 1 de Fator de Crescimento de Fibroblastos/metabolismo , Receptor alfa de Fator de Crescimento Derivado de Plaquetas/metabolismo , Sulfonamidas/farmacologia , Sunitinibe
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