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1.
Nature ; 569(7754): 131-135, 2019 05.
Artigo em Inglês | MEDLINE | ID: mdl-30996350

RESUMO

Pancreatic ductal adenocarcinoma (PDAC) has a dismal prognosis largely owing to inefficient diagnosis and tenacious drug resistance. Activation of pancreatic stellate cells (PSCs) and consequent development of dense stroma are prominent features accounting for this aggressive biology1,2. The reciprocal interplay between PSCs and pancreatic cancer cells (PCCs) not only enhances tumour progression and metastasis but also sustains their own activation, facilitating a vicious cycle to exacerbate tumorigenesis and drug resistance3-7. Furthermore, PSC activation occurs very early during PDAC tumorigenesis8-10, and activated PSCs comprise a substantial fraction of the tumour mass, providing a rich source of readily detectable factors. Therefore, we hypothesized that the communication between PSCs and PCCs could be an exploitable target to develop effective strategies for PDAC therapy and diagnosis. Here, starting with a systematic proteomic investigation of secreted disease mediators and underlying molecular mechanisms, we reveal that leukaemia inhibitory factor (LIF) is a key paracrine factor from activated PSCs acting on cancer cells. Both pharmacologic LIF blockade and genetic Lifr deletion markedly slow tumour progression and augment the efficacy of chemotherapy to prolong survival of PDAC mouse models, mainly by modulating cancer cell differentiation and epithelial-mesenchymal transition status. Moreover, in both mouse models and human PDAC, aberrant production of LIF in the pancreas is restricted to pathological conditions and correlates with PDAC pathogenesis, and changes in the levels of circulating LIF correlate well with tumour response to therapy. Collectively, these findings reveal a function of LIF in PDAC tumorigenesis, and suggest its translational potential as an attractive therapeutic target and circulating marker. Our studies underscore how a better understanding of cell-cell communication within the tumour microenvironment can suggest novel strategies for cancer therapy.


Assuntos
Carcinoma Ductal Pancreático/tratamento farmacológico , Carcinoma Ductal Pancreático/patologia , Fator Inibidor de Leucemia/metabolismo , Neoplasias Pancreáticas/tratamento farmacológico , Neoplasias Pancreáticas/patologia , Comunicação Parácrina , Animais , Anticorpos Monoclonais/imunologia , Anticorpos Monoclonais/farmacologia , Anticorpos Monoclonais/uso terapêutico , Carcinogênese/genética , Carcinoma Ductal Pancreático/diagnóstico , Diferenciação Celular/efeitos dos fármacos , Diferenciação Celular/imunologia , Linhagem Celular Tumoral , Progressão da Doença , Resistencia a Medicamentos Antineoplásicos , Transição Epitelial-Mesenquimal , Feminino , Humanos , Fator Inibidor de Leucemia/antagonistas & inibidores , Fator Inibidor de Leucemia/sangue , Masculino , Espectrometria de Massas , Camundongos , Neoplasias Pancreáticas/diagnóstico , Comunicação Parácrina/efeitos dos fármacos , Receptores de OSM-LIF/deficiência , Receptores de OSM-LIF/genética , Receptores de OSM-LIF/metabolismo , Microambiente Tumoral
3.
Gastroenterology ; 159(5): 1866-1881.e8, 2020 11.
Artigo em Inglês | MEDLINE | ID: mdl-32717220

RESUMO

BACKGROUND & AIMS: Development of pancreatic ductal adenocarcinoma (PDA) involves acinar to ductal metaplasia and genesis of tuft cells. It has been a challenge to study these rare cells because of the lack of animal models. We investigated the role of tuft cells in pancreatic tumorigenesis. METHODS: We performed studies with LSL-KrasG12D/+;Ptf1aCre/+ mice (KC; develop pancreatic tumors), KC mice crossed with mice with pancreatic disruption of Pou2f3 (KPouC mice; do not develop tuft cells), or mice with pancreatic disruption of the hematopoietic prostaglandin D synthase gene (Hpgds, KHC mice) and wild-type mice. Mice were allowed to age or were given caerulein to induce pancreatitis; pancreata were collected and analyzed by histology, immunohistochemistry, RNA sequencing, ultrastructural microscopy, and metabolic profiling. We performed laser-capture dissection and RNA-sequencing analysis of pancreatic tissues from 26 patients with pancreatic intraepithelial neoplasia (PanIN), 19 patients with intraductal papillary mucinous neoplasms (IPMNs), and 197 patients with PDA. RESULTS: Pancreata from KC mice had increased formation of tuft cells and higher levels of prostaglandin D2 than wild-type mice. Pancreas-specific deletion of POU2F3 in KC mice (KPouC mice) resulted in a loss of tuft cells and accelerated tumorigenesis. KPouC mice had increased fibrosis and activation of immune cells after administration of caerulein. Pancreata from KPouC and KHC mice had significantly lower levels of prostaglandin D2, compared with KC mice, and significantly increased numbers of PanINs and PDAs. KPouC and KHC mice had increased pancreatic injury after administration of caerulein, significantly less normal tissue, more extracellular matrix deposition, and higher PanIN grade than KC mice. Human PanIN and intraductal papillary mucinous neoplasm had gene expression signatures associated with tuft cells and increased expression of Hpgds messenger RNA compared with PDA. CONCLUSIONS: In mice with KRAS-induced pancreatic tumorigenesis, loss of tuft cells accelerates tumorigenesis and increases the severity of caerulein-induced pancreatic injury, via decreased production of prostaglandin D2. These data are consistent with the hypothesis that tuft cells are a metaplasia-induced tumor attenuating cell type.


Assuntos
Carcinoma Ductal Pancreático/prevenção & controle , Transformação Celular Neoplásica/metabolismo , Pâncreas/metabolismo , Neoplasias Pancreáticas/prevenção & controle , Prostaglandina D2/metabolismo , Animais , Carcinoma Ductal Pancreático/genética , Carcinoma Ductal Pancreático/metabolismo , Carcinoma Ductal Pancreático/patologia , Transformação Celular Neoplásica/genética , Transformação Celular Neoplásica/patologia , Ceruletídeo , Modelos Animais de Doenças , Metabolismo Energético , Fibrose , Humanos , Interleucinas/genética , Interleucinas/metabolismo , Oxirredutases Intramoleculares/genética , Oxirredutases Intramoleculares/metabolismo , Camundongos Transgênicos , Mutação , Fatores de Transcrição de Octâmero/genética , Fatores de Transcrição de Octâmero/metabolismo , Pâncreas/patologia , Neoplasias Pancreáticas/genética , Neoplasias Pancreáticas/metabolismo , Neoplasias Pancreáticas/patologia , Pancreatite/induzido quimicamente , Pancreatite/genética , Pancreatite/metabolismo , Pancreatite/patologia , Proteínas Proto-Oncogênicas p21(ras)/genética , Fatores de Tempo , Fatores de Transcrição/genética , Fatores de Transcrição/metabolismo
4.
Nucleic Acids Res ; 40(18): 8927-41, 2012 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-22790984

RESUMO

Acute leukemias are characterized by deregulation of transcriptional networks that control the lineage specificity of gene expression. The aberrant overexpression of the Spi-1/PU.1 transcription factor leads to erythroleukemia. To determine how Spi-1 mechanistically influences the transcriptional program, we combined a ChIP-seq analysis with transcriptional profiling in cells from an erythroleukemic mouse model. We show that Spi-1 displays a selective DNA-binding that does not often cause transcriptional modulation. We report that Spi-1 controls transcriptional activation and repression partially through distinct Spi-1 recruitment to chromatin. We revealed several parameters impacting on Spi-1-mediated transcriptional activation. Gene activation is facilitated by Spi-1 occupancy close to transcriptional starting site of genes devoid of CGIs. Moreover, in those regions Spi-1 acts by binding to multiple motifs tightly clustered and with similar orientation. Finally, in contrast to the myeloid and lymphoid B cells in which Spi-1 exerts a physiological activity, in the erythroleukemic cells, lineage-specific cooperating factors do not play a prevalent role in Spi-1-mediated transcriptional activation. Thus, our work describes a new mechanism of gene activation through clustered site occupancy of Spi-1 particularly relevant in regard to the strong expression of Spi-1 in the erythroleukemic cells.


Assuntos
Leucemia Eritroblástica Aguda/genética , Proteínas Proto-Oncogênicas/metabolismo , Elementos Reguladores de Transcrição , Transativadores/metabolismo , Ativação Transcricional , Animais , Sítios de Ligação , Linhagem Celular Tumoral , Imunoprecipitação da Cromatina , Ilhas de CpG , DNA/química , DNA/metabolismo , Perfilação da Expressão Gênica , Regulação Neoplásica da Expressão Gênica , Genoma , Leucemia Eritroblástica Aguda/metabolismo , Camundongos , Camundongos Transgênicos , Motivos de Nucleotídeos , Análise de Sequência de DNA , Sítio de Iniciação de Transcrição
5.
Oncotarget ; 8(23): 37104-37114, 2017 Jun 06.
Artigo em Inglês | MEDLINE | ID: mdl-28415748

RESUMO

Oncogenes trigger replicative stress that can lead to genetic instability, which participates in cancer progression. Thus, determining how cells cope with replicative stress can help our understanding of oncogenesis and lead to the identification of new antitumor treatment targets. We previously showed that constitutive overexpression of the oncogenic transcription factor Spi1/PU.1 leads to pre-leukemic cells that have a shortened S phase duration with an increased replication fork speed and increased mutability in the absence of DNA breaks. Here, we demonstrate that the S phase checkpoint protein CHK1 is maintained in a low phosphorylation state in Spi1/PU.1-overexpressing cells and provide evidence that this is not due to negative control of its primary kinase ATR. Notably, we found that the expression of the CHK1 phosphatase PP1α is increased in Spi1/PU.1-overexpressing cells. By exogenously modulating its activity, we demonstrate that PP1α is required to maintain CHK1 in a dephosphorylated state and, more importantly, that it is responsible for the accelerated replication fork progression in Spi1/PU.1-overexpressing cells. These results identify a novel pathway by which an oncogene influences replication in the absence of DNA damage.


Assuntos
Quinase 1 do Ponto de Checagem/metabolismo , Replicação do DNA , Proteína Fosfatase 1/metabolismo , Proteínas Proto-Oncogênicas/metabolismo , Transativadores/metabolismo , Animais , Ciclo Celular/genética , Células Cultivadas , Quinase 1 do Ponto de Checagem/genética , Regulação Leucêmica da Expressão Gênica , Humanos , Células K562 , Leucemia/genética , Leucemia/metabolismo , Leucemia/patologia , Camundongos Transgênicos , Fosforilação , Proteína Fosfatase 1/genética , Proteínas Proto-Oncogênicas/genética , Interferência de RNA , Transativadores/genética
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