Your browser doesn't support javascript.
loading
Mostrar: 20 | 50 | 100
Resultados 1 - 4 de 4
Filtrar
2.
Nat Commun ; 14(1): 4387, 2023 07 20.
Artigo em Inglês | MEDLINE | ID: mdl-37474499

RESUMO

The drivers of recurrence and resistance in ovarian high grade serous carcinoma remain unclear. We investigate the acquisition of resistance by collecting tumour biopsies from a cohort of 276 women with relapsed ovarian high grade serous carcinoma in the BriTROC-1 study. Panel sequencing shows close concordance between diagnosis and relapse, with only four discordant cases. There is also very strong concordance in copy number between diagnosis and relapse, with no significant difference in purity, ploidy or focal somatic copy number alterations, even when stratified by platinum sensitivity or prior chemotherapy lines. Copy number signatures are strongly correlated with immune cell infiltration, whilst diagnosis samples from patients with primary platinum resistance have increased rates of CCNE1 and KRAS amplification and copy number signature 1 exposure. Our data show that the ovarian high grade serous carcinoma genome is remarkably stable between diagnosis and relapse and acquired chemotherapy resistance does not select for common copy number drivers.


Assuntos
Cistadenocarcinoma Seroso , Neoplasias Ovarianas , Humanos , Feminino , Neoplasias Ovarianas/tratamento farmacológico , Neoplasias Ovarianas/genética , Neoplasias Ovarianas/patologia , Variações do Número de Cópias de DNA/genética , Recidiva Local de Neoplasia/genética , Mutação , Cistadenocarcinoma Seroso/tratamento farmacológico , Cistadenocarcinoma Seroso/genética , Cistadenocarcinoma Seroso/patologia
3.
Nat Genet ; 52(6): 582-593, 2020 06.
Artigo em Inglês | MEDLINE | ID: mdl-32483290

RESUMO

In metastatic cancer, the degree of heterogeneity of the tumor microenvironment (TME) and its molecular underpinnings remain largely unstudied. To characterize the tumor-immune interface at baseline and during neoadjuvant chemotherapy (NACT) in high-grade serous ovarian cancer (HGSOC), we performed immunogenomic analysis of treatment-naive and paired samples from before and after treatment with chemotherapy. In treatment-naive HGSOC, we found that immune-cell-excluded and inflammatory microenvironments coexist within the same individuals and within the same tumor sites, indicating ubiquitous variability in immune cell infiltration. Analysis of TME cell composition, DNA copy number, mutations and gene expression showed that immune cell exclusion was associated with amplification of Myc target genes and increased expression of canonical Wnt signaling in treatment-naive HGSOC. Following NACT, increased natural killer (NK) cell infiltration and oligoclonal expansion of T cells were detected. We demonstrate that the tumor-immune microenvironment of advanced HGSOC is intrinsically heterogeneous and that chemotherapy induces local immune activation, suggesting that chemotherapy can potentiate the immunogenicity of immune-excluded HGSOC tumors.


Assuntos
Cistadenocarcinoma Seroso/tratamento farmacológico , Regulação Neoplásica da Expressão Gênica , Neoplasias Ovarianas/tratamento farmacológico , Microambiente Tumoral/imunologia , Animais , Cisplatino/imunologia , Cisplatino/farmacologia , Estudos de Coortes , Cistadenocarcinoma Seroso/genética , Cistadenocarcinoma Seroso/imunologia , Variações do Número de Cópias de DNA , Feminino , Perfilação da Expressão Gênica/estatística & dados numéricos , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Genes myc , Humanos , Células Matadoras Naturais/efeitos dos fármacos , Linfócitos do Interstício Tumoral/imunologia , Linfócitos do Interstício Tumoral/patologia , Camundongos , Mutação , Neoplasias Ovarianas/genética , Neoplasias Ovarianas/imunologia , Análise de Componente Principal , Microambiente Tumoral/efeitos dos fármacos , Microambiente Tumoral/genética , Via de Sinalização Wnt
4.
Nat Med ; 23(12): 1424-1435, 2017 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-29131160

RESUMO

Human liver cancer research currently lacks in vitro models that can faithfully recapitulate the pathophysiology of the original tumor. We recently described a novel, near-physiological organoid culture system, wherein primary human healthy liver cells form long-term expanding organoids that retain liver tissue function and genetic stability. Here we extend this culture system to the propagation of primary liver cancer (PLC) organoids from three of the most common PLC subtypes: hepatocellular carcinoma (HCC), cholangiocarcinoma (CC) and combined HCC/CC (CHC) tumors. PLC-derived organoid cultures preserve the histological architecture, gene expression and genomic landscape of the original tumor, allowing for discrimination between different tumor tissues and subtypes, even after long-term expansion in culture in the same medium conditions. Xenograft studies demonstrate that the tumorogenic potential, histological features and metastatic properties of PLC-derived organoids are preserved in vivo. PLC-derived organoids are amenable for biomarker identification and drug-screening testing and led to the identification of the ERK inhibitor SCH772984 as a potential therapeutic agent for primary liver cancer. We thus demonstrate the wide-ranging biomedical utilities of PLC-derived organoid models in furthering the understanding of liver cancer biology and in developing personalized-medicine approaches for the disease.


Assuntos
Neoplasias dos Ductos Biliares/patologia , Carcinoma Hepatocelular/patologia , Colangiocarcinoma/patologia , Ensaios de Seleção de Medicamentos Antitumorais/métodos , Neoplasias Hepáticas/patologia , Organoides/patologia , Cultura Primária de Células/métodos , Animais , Antineoplásicos/isolamento & purificação , Antineoplásicos/uso terapêutico , Neoplasias dos Ductos Biliares/tratamento farmacológico , Neoplasias dos Ductos Biliares/genética , Carcinoma Hepatocelular/tratamento farmacológico , Carcinoma Hepatocelular/genética , Proliferação de Células , Colangiocarcinoma/tratamento farmacológico , Colangiocarcinoma/genética , Regulação Neoplásica da Expressão Gênica , Humanos , Neoplasias Hepáticas/tratamento farmacológico , Neoplasias Hepáticas/genética , Masculino , Camundongos , Camundongos Endogâmicos NOD , Camundongos SCID , Medicina de Precisão , Transcriptoma , Células Tumorais Cultivadas , Ensaios Antitumorais Modelo de Xenoenxerto
SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA
...