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1.
Nat Chem Biol ; 18(12): 1388-1398, 2022 12.
Artigo em Inglês | MEDLINE | ID: mdl-36097295

RESUMO

The Janus tyrosine kinase (JAK) family of non-receptor tyrosine kinases includes four isoforms (JAK1, JAK2, JAK3, and TYK2) and is responsible for signal transduction downstream of diverse cytokine receptors. JAK inhibitors have emerged as important therapies for immun(onc)ological disorders, but their use is limited by undesirable side effects presumed to arise from poor isoform selectivity, a common challenge for inhibitors targeting the ATP-binding pocket of kinases. Here we describe the chemical proteomic discovery of a druggable allosteric cysteine present in the non-catalytic pseudokinase domain of JAK1 (C817) and TYK2 (C838), but absent from JAK2 or JAK3. Electrophilic compounds selectively engaging this site block JAK1-dependent trans-phosphorylation and cytokine signaling, while appearing to act largely as 'silent' ligands for TYK2. Importantly, the allosteric JAK1 inhibitors do not impair JAK2-dependent cytokine signaling and are inactive in cells expressing a C817A JAK1 mutant. Our findings thus reveal an allosteric approach for inhibiting JAK1 with unprecedented isoform selectivity.


Assuntos
Cisteína , Proteômica , Transdução de Sinais , Citocinas , Isoformas de Proteínas
2.
Genes Dev ; 30(24): 2669-2683, 2016 12 15.
Artigo em Inglês | MEDLINE | ID: mdl-28087712

RESUMO

Aberrant activation of embryonic signaling pathways is frequent in pancreatic ductal adenocarcinoma (PDA), making developmental regulators therapeutically attractive. Here we demonstrate diverse functions for pancreatic and duodenal homeobox 1 (PDX1), a transcription factor indispensable for pancreas development, in the progression from normal exocrine cells to metastatic PDA. We identify a critical role for PDX1 in maintaining acinar cell identity, thus resisting the formation of pancreatic intraepithelial neoplasia (PanIN)-derived PDA. Upon neoplastic transformation, the role of PDX1 changes from tumor-suppressive to oncogenic. Interestingly, subsets of malignant cells lose PDX1 expression while undergoing epithelial-to-mesenchymal transition (EMT), and PDX1 loss is associated with poor outcome. This stage-specific functionality arises from profound shifts in PDX1 chromatin occupancy from acinar cells to PDA. In summary, we report distinct roles of PDX1 at different stages of PDA, suggesting that therapeutic approaches against this potential target need to account for its changing functions at different stages of carcinogenesis. These findings provide insight into the complexity of PDA pathogenesis and advocate a rigorous investigation of therapeutically tractable targets at distinct phases of PDA development and progression.


Assuntos
Carcinoma Ductal Pancreático/genética , Transformação Celular Neoplásica/genética , Regulação Neoplásica da Expressão Gênica , Proteínas de Homeodomínio/metabolismo , Neoplasias Pancreáticas/genética , Transativadores/metabolismo , Células Acinares/patologia , Animais , Carcinoma Ductal Pancreático/fisiopatologia , Deleção de Genes , Proteínas de Homeodomínio/genética , Humanos , Camundongos , Neoplasias Pancreáticas/fisiopatologia , Análise Serial de Tecidos , Transativadores/genética , Células Tumorais Cultivadas
3.
Genes Dev ; 29(6): 658-71, 2015 Mar 15.
Artigo em Inglês | MEDLINE | ID: mdl-25792600

RESUMO

Pancreatic ductal adenocarcinoma (PDA) develops predominantly through pancreatic intraepithelial neoplasia (PanIN) and intraductal papillary mucinous neoplasm (IPMN) precursor lesions. Pancreatic acinar cells are reprogrammed to a "ductal-like" state during PanIN-PDA formation. Here, we demonstrate a parallel mechanism operative in mature duct cells during which functional cells undergo "ductal retrogression" to form IPMN-PDA. We further identify critical antagonistic roles for Brahma-related gene 1 (Brg1), a catalytic subunit of the SWI/SNF complexes, during IPMN-PDA development. In mature duct cells, Brg1 inhibits the dedifferentiation that precedes neoplastic transformation, thus attenuating tumor initiation. In contrast, Brg1 promotes tumorigenesis in full-blown PDA by supporting a mesenchymal-like transcriptional landscape. We further show that JQ1, a drug that is currently being tested in clinical trials for hematological malignancies, impairs PDA tumorigenesis by both mimicking some and inhibiting other Brg1-mediated functions. In summary, our study demonstrates the context-dependent roles of Brg1 and points to potential therapeutic treatment options based on epigenetic regulation in PDA.


Assuntos
Carcinoma Ductal Pancreático/fisiopatologia , Transformação Celular Neoplásica/genética , DNA Helicases/metabolismo , Proteínas Nucleares/metabolismo , Neoplasias Pancreáticas/fisiopatologia , Fatores de Transcrição/metabolismo , Animais , Azepinas/farmacologia , Azepinas/uso terapêutico , Carcinoma Ductal Pancreático/tratamento farmacológico , Transformação Celular Neoplásica/efeitos dos fármacos , DNA Helicases/genética , Regulação Neoplásica da Expressão Gênica , Humanos , Camundongos , Proteínas Nucleares/genética , Neoplasias Pancreáticas/tratamento farmacológico , Proteínas Proto-Oncogênicas p21(ras)/metabolismo , Fatores de Transcrição SOX9/genética , Fatores de Transcrição SOX9/metabolismo , Fatores de Transcrição/genética , Triazóis/farmacologia , Triazóis/uso terapêutico , Células Tumorais Cultivadas
5.
Pancreatology ; 17(3): 350-353, 2017.
Artigo em Inglês | MEDLINE | ID: mdl-28473229

RESUMO

OBJECTIVES: Pancreatic ductal adenocarcinoma (PDAC) is thought to derive from different precursor lesions including the recently identified atypical flat lesions (AFL). While all precursor lesions and PDAC share ductal characteristics, there is an ongoing debate about the cellular origin of the different PDAC precursor lesions. In particular, pancreatic acinar cells have previously been shown to display a remarkable plasticity being able to undergo ductal dedifferentiation in the context of oncogenic stimuli. METHODS: Histological analyses were performed in a murine PDAC model that specifically expresses oncogenic Kras in adult pancreatic acinar cells. Occurrence, characterization, and lineage tracing of AFLs were investigated. RESULTS: Upon expression of oncogenic Kras in adult pancreatic acinar cells, AFLs with typical morphology and expression profile arise. Lineage tracing confirmed that the AFLs were of acinar origin. CONCLUSIONS: Using a murine PDAC model, this study identifies pancreatic acinar cells as a cellular source for AFLs.


Assuntos
Células Acinares/patologia , Carcinoma Ductal Pancreático/patologia , Neoplasias Pancreáticas/patologia , Animais , Carcinoma Ductal Pancreático/induzido quimicamente , Carcinoma Ductal Pancreático/metabolismo , Diferenciação Celular , Transformação Celular Neoplásica/patologia , Antagonistas de Estrogênios , Imuno-Histoquímica , Camundongos , Neoplasias Pancreáticas/induzido quimicamente , Neoplasias Pancreáticas/metabolismo , Proteínas Proto-Oncogênicas p21(ras)/biossíntese , Proteínas Proto-Oncogênicas p21(ras)/genética , Tamoxifeno
6.
J Biol Chem ; 287(5): 3019-28, 2012 Jan 27.
Artigo em Inglês | MEDLINE | ID: mdl-22167187

RESUMO

Exposure to ultraviolet rays (UV) in sunlight is the main cause of skin cancer. Here, we show that the p53-induced genes DDB2 and p21 are down-regulated in skin cancer, and in the mouse model they functionally cooperate to prevent UV-induced skin cancer. Our previous studies demonstrated an antagonistic role of DDB2 and p21 in nucleotide excision repair and apoptosis. Surprisingly, we find that the loss of p21 restores nucleotide excision repair and apoptosis in Ddb2(-/-) mice, but it does not protect from UV-mediated skin carcinogenesis. In contrast, Ddb2(-/-)p21(-/-) mice are significantly more susceptible to UV-induced skin cancer than the Ddb2(-/-) or the p21(-/-) mice. We provide evidence that p21 deletion in the Ddb2(-/-) background causes a strong increase in cell proliferation. The increased proliferation in the Ddb2(-/-)p21(-/-) background is related to a severe deficiency in UV-induced premature senescence. Also, the oncogenic pro-proliferation transcription factor FOXM1 is overexpressed in the p21(-/-) background. Our results show that the anti-proliferative and the pro-senescence pathways of DDB2 and p21 are critical protection mechanisms against skin malignancies.


Assuntos
Inibidor de Quinase Dependente de Ciclina p21/metabolismo , Neoplasias Induzidas por Radiação/metabolismo , Neoplasias Cutâneas/metabolismo , Proteína Supressora de Tumor p53/metabolismo , Raios Ultravioleta/efeitos adversos , Animais , Proliferação de Células/efeitos da radiação , Senescência Celular/genética , Senescência Celular/efeitos da radiação , Inibidor de Quinase Dependente de Ciclina p21/genética , Reparo do DNA/genética , Reparo do DNA/efeitos da radiação , Proteínas de Ligação a DNA , Proteína Forkhead Box M1 , Fatores de Transcrição Forkhead/genética , Fatores de Transcrição Forkhead/metabolismo , Deleção de Genes , Camundongos , Camundongos Knockout , Neoplasias Induzidas por Radiação/genética , Neoplasias Induzidas por Radiação/patologia , Neoplasias Cutâneas/genética , Neoplasias Cutâneas/patologia , Proteína Supressora de Tumor p53/genética
7.
Dev Biol ; 352(2): 278-87, 2011 Apr 15.
Artigo em Inglês | MEDLINE | ID: mdl-21291880

RESUMO

The mammalian Cul4 genes, Cul4A and Cul4B, encode the scaffold components of the cullin-based E3 ubiquitin ligases. The two Cul4 genes are functionally redundant. Recent study indicated that mice expressing a truncated CUL4A that fails to interact with its functional partner ROC1 exhibit no developmental phenotype. We generated a Cul4A-/- strain lacking exons 4-8 that does not express any detectable truncated protein. In this strain, the male mice are infertile and exhibit severe deficiencies in spermatogenesis. The primary spermatocytes are deficient in progression through late prophase I, a time point when expression of the X-linked Cul4B gene is silenced due to meiotic sex chromosome inactivation. Testes of the Cul4A-/- mice exhibit extensive apoptosis. Interestingly, the pachytene spermatocytes exhibit persistent double stranded breaks, suggesting a deficiency in homologous recombination. Also, we find that CUL4A localizes to the double stranded breaks generated in pre-pachytene spermatocytes. The observations identify a novel function of CUL4A in meiotic recombination and demonstrate an essential role of CUL4A in spermatogenesis.


Assuntos
Proteínas Culina/fisiologia , Fertilidade/fisiologia , Espermatogênese/fisiologia , Animais , Apoptose , Sequência de Bases , Proteínas Culina/genética , Quebras de DNA de Cadeia Dupla , Primers do DNA/genética , Reparo do DNA/genética , Reparo do DNA/fisiologia , Fertilidade/genética , Masculino , Meiose/genética , Meiose/fisiologia , Prófase Meiótica I/genética , Prófase Meiótica I/fisiologia , Camundongos , Camundongos Knockout , Recombinação Genética , Espermatócitos/citologia , Espermatócitos/fisiologia , Espermatogênese/genética , Testículo/anormalidades
8.
Proc Natl Acad Sci U S A ; 106(26): 10690-5, 2009 Jun 30.
Artigo em Inglês | MEDLINE | ID: mdl-19541625

RESUMO

The xeroderma pigmentosum complementation group E (XP-E) gene product damaged-DNA binding protein 2 (DDB2) plays important roles in nucleotide excision repair (NER). Previously, we showed that DDB2 participates in NER by regulating the level of p21(Waf1/Cip1). Here we show that the p21(Waf1/Cip1) -regulatory function of DDB2 plays a central role in defining the response (apoptosis or arrest) to DNA damage. The DDB2-deficient cells are resistant to apoptosis in response to a variety of DNA-damaging agents, despite activation of p53 and the pro-apoptotic genes. Instead, these cells undergo cell cycle arrest. Also, the DDB2-deficient cells are resistant to E2F1-induced apoptosis. The resistance to apoptosis of the DDB2-deficient cells is caused by an increased accumulation of p21(Waf1/Cip1) after DNA damage. We provide evidence that DDB2 targets p21(Waf1/Cip1) for proteolysis. The resistance to apoptosis in DDB2-deficient cells also involves Mdm2 in a manner that is distinct from the p53-regulatory activity of Mdm2. Our results provide evidence for a new regulatory loop involving the NER protein DDB2, Mdm2, and p21(Waf1/Cip1) that is critical in deciding cell fate (apoptosis or arrest) upon DNA damage.


Assuntos
Apoptose/fisiologia , Ciclo Celular/fisiologia , Dano ao DNA/fisiologia , Proteínas de Ligação a DNA/metabolismo , Aclarubicina/farmacologia , Animais , Antineoplásicos/farmacologia , Western Blotting , Células Cultivadas , Cisplatino/farmacologia , Inibidor de Quinase Dependente de Ciclina p21/genética , Inibidor de Quinase Dependente de Ciclina p21/metabolismo , Reparo do DNA , Proteínas de Ligação a DNA/genética , Fibroblastos/efeitos dos fármacos , Fibroblastos/metabolismo , Fibroblastos/efeitos da radiação , Citometria de Fluxo , Células HeLa , Humanos , Marcação In Situ das Extremidades Cortadas , Camundongos , Camundongos Knockout , Proteínas Proto-Oncogênicas c-mdm2/genética , Proteínas Proto-Oncogênicas c-mdm2/metabolismo , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Proteína Supressora de Tumor p53/genética , Proteína Supressora de Tumor p53/metabolismo , Raios Ultravioleta
9.
Int J Mol Sci ; 13(9): 11012-11026, 2012.
Artigo em Inglês | MEDLINE | ID: mdl-23109835

RESUMO

Premature senescence induced by DNA damage or oncogene is a critical mechanism of tumor suppression. Reactive oxygen species (ROS) have been implicated in the induction of premature senescence response. Several pathological disorders such as cancer, aging and age related neurological abnormalities have been linked to ROS deregulation. Here, we discuss how Damaged DNA binding Protein-2 (DDB2), a nucleotide excision repair protein, plays an important role in ROS regulation by epigenetically repressing the antioxidant genes MnSOD and Catalase. We further revisit a model in which DDB2 plays an instrumental role in DNA damage induced ROS accumulation, ROS induced premature senescence and inhibition of skin tumorigenesis.


Assuntos
Senilidade Prematura/genética , Senescência Celular/genética , Dano ao DNA/genética , Proteínas de Ligação a DNA/genética , Espécies Reativas de Oxigênio/metabolismo , Animais , Apoptose/genética , Proteínas Mutadas de Ataxia Telangiectasia/metabolismo , Catalase/biossíntese , Catalase/genética , Transformação Celular Neoplásica , Proteínas Culina/metabolismo , Reparo do DNA/genética , Proteínas de Ligação a DNA/metabolismo , Humanos , Camundongos , Transdução de Sinais/genética , Neoplasias Cutâneas/patologia , Superóxido Dismutase/biossíntese , Superóxido Dismutase/genética , Xeroderma Pigmentoso/genética
10.
Diabetes ; 68(9): 1806-1818, 2019 09.
Artigo em Inglês | MEDLINE | ID: mdl-31201281

RESUMO

Transcription factors positively and/or negatively impact gene expression by recruiting coregulatory factors, which interact through protein-protein binding. Here we demonstrate that mouse pancreas size and islet ß-cell function are controlled by the ATP-dependent Swi/Snf chromatin remodeling coregulatory complex that physically associates with Pdx1, a diabetes-linked transcription factor essential to pancreatic morphogenesis and adult islet cell function and maintenance. Early embryonic deletion of just the Swi/Snf Brg1 ATPase subunit reduced multipotent pancreatic progenitor cell proliferation and resulted in pancreas hypoplasia. In contrast, removal of both Swi/Snf ATPase subunits, Brg1 and Brm, was necessary to compromise adult islet ß-cell activity, which included whole-animal glucose intolerance, hyperglycemia, and impaired insulin secretion. Notably, lineage-tracing analysis revealed Swi/Snf-deficient ß-cells lost the ability to produce the mRNAs for Ins and other key metabolic genes without effecting the expression of many essential islet-enriched transcription factors. Swi/Snf was necessary for Pdx1 to bind to the Ins gene enhancer, demonstrating the importance of this association in mediating chromatin accessibility. These results illustrate how fundamental the Pdx1:Swi/Snf coregulator complex is in the pancreas, and we discuss how disrupting their association could influence type 1 and type 2 diabetes susceptibility.


Assuntos
Proliferação de Células/fisiologia , Montagem e Desmontagem da Cromatina/fisiologia , DNA Helicases/metabolismo , Proteínas de Homeodomínio/metabolismo , Células Secretoras de Insulina/metabolismo , Proteínas Nucleares/metabolismo , Pâncreas/metabolismo , Transativadores/metabolismo , Fatores de Transcrição/metabolismo , Animais , DNA Helicases/genética , Regulação da Expressão Gênica , Intolerância à Glucose/genética , Intolerância à Glucose/metabolismo , Proteínas de Homeodomínio/genética , Insulina/sangue , Células Secretoras de Insulina/citologia , Camundongos , Camundongos Transgênicos , Proteínas Nucleares/genética , Pâncreas/citologia , Transativadores/genética , Fatores de Transcrição/genética
12.
Nat Commun ; 9(1): 485, 2018 02 02.
Artigo em Inglês | MEDLINE | ID: mdl-29396395

RESUMO

Pancreatic ß cells are highly specialized to regulate systemic glucose levels by secreting insulin. In adults, increase in ß-cell mass is limited due to brakes on cell replication. In contrast, proliferation is robust in neonatal ß cells that are functionally immature as defined by a lower set point for glucose-stimulated insulin secretion. Here we show that ß-cell proliferation and immaturity are linked by tuning expression of physiologically relevant, non-oncogenic levels of c-Myc. Adult ß cells induced to replicate adopt gene expression and metabolic profiles resembling those of immature neonatal ß that proliferate readily. We directly demonstrate that priming insulin-producing cells to enter the cell cycle promotes a functionally immature phenotype. We suggest that there exists a balance between mature functionality and the ability to expand, as the phenotypic state of the ß cell reverts to a less functional one in response to proliferative cues.


Assuntos
Proliferação de Células/genética , Células Secretoras de Insulina/citologia , Proteínas Proto-Oncogênicas c-myc/genética , Animais , Ciclo Celular , Diferenciação Celular/genética , Divisão Celular/genética , Expressão Gênica , Insulina/metabolismo , Secreção de Insulina , Células Secretoras de Insulina/metabolismo , Ilhotas Pancreáticas/citologia , Camundongos , Camundongos Transgênicos , Fenótipo
13.
J Clin Invest ; 128(8): 3475-3489, 2018 08 01.
Artigo em Inglês | MEDLINE | ID: mdl-30010625

RESUMO

Chromatin remodeler Brahma related gene 1 (BRG1) is silenced in approximately 10% of human pancreatic ductal adenocarcinomas (PDAs). We previously showed that BRG1 inhibits the formation of intraductal pancreatic mucinous neoplasm (IPMN) and that IPMN-derived PDA originated from ductal cells. However, the role of BRG1 in pancreatic intraepithelial neoplasia-derived (PanIN-derived) PDA that originated from acinar cells remains elusive. Here, we found that exclusive elimination of Brg1 in acinar cells of Ptf1a-CreER; KrasG12D; Brg1fl/fl mice impaired the formation of acinar-to-ductal metaplasia (ADM) and PanIN independently of p53 mutation, while PDA formation was inhibited in the presence of p53 mutation. BRG1 bound to regions of the Sox9 promoter to regulate its expression and was critical for recruitment of upstream regulators, including PDX1, to the Sox9 promoter and enhancer in acinar cells. SOX9 expression was downregulated in BRG1-depleted ADMs/PanINs. Notably, Sox9 overexpression canceled this PanIN-attenuated phenotype in KBC mice. Furthermore, Brg1 deletion in established PanIN by using a dual recombinase system resulted in regression of the lesions in mice. Finally, BRG1 expression correlated with SOX9 expression in human PDAs. In summary, BRG1 is critical for PanIN initiation and progression through positive regulation of SOX9. Thus, the BRG1/SOX9 axis is a potential target for PanIN-derived PDA.


Assuntos
Carcinoma Ductal Pancreático/metabolismo , Transformação Celular Neoplásica/metabolismo , DNA Helicases/biossíntese , Proteínas Nucleares/biossíntese , Neoplasias Pancreáticas/metabolismo , Fatores de Transcrição SOX9/metabolismo , Transdução de Sinais , Fatores de Transcrição/biossíntese , Animais , Carcinoma Ductal Pancreático/genética , Carcinoma Ductal Pancreático/patologia , Transformação Celular Neoplásica/genética , Transformação Celular Neoplásica/patologia , DNA Helicases/genética , Feminino , Regulação da Expressão Gênica , Humanos , Masculino , Camundongos , Camundongos Transgênicos , Proteínas Nucleares/genética , Neoplasias Pancreáticas/genética , Neoplasias Pancreáticas/patologia , Elementos de Resposta , Fatores de Transcrição SOX9/genética , Fatores de Transcrição/genética , Proteína Supressora de Tumor p53/genética , Proteína Supressora de Tumor p53/metabolismo , Neoplasias Pancreáticas
14.
Epigenetics ; 13(4): 449-457, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-30056798

RESUMO

International experts gathered at the Mayo Clinic (Rochester MN, USA) on February 27th-28th, 2017 for a meeting entitled 'Basic and Translational Facets of the Epigenetics of GI Diseases'. This workshop summarized recent advances on the role of epigenetics in the pathobiology of gastrointestinal (GI) diseases. Highlights of the meeting included recent advances on the involvement of different epigenetic mechanisms in malignant and nonmalignant GI disorders and the epigenetic heterogeneity exhibited in these diseases. The translational value of epigenetic drugs, as well as the current and future use of epigenetic changes (i.e., DNA methylation patterns) as biomarkers for early detection tools or disease stratification were also important topics of discussion.


Assuntos
Epigênese Genética , Gastroenteropatias/genética , Metilação de DNA , Heterogeneidade Genética , Marcadores Genéticos , Humanos , Pesquisa Translacional Biomédica
15.
Clin Cancer Res ; 23(16): 4865-4874, 2017 Aug 15.
Artigo em Inglês | MEDLINE | ID: mdl-28424202

RESUMO

Purpose: Pancreatic cysts are estimated to be present in 2%-3% of the adult population. Unfortunately, current diagnostics do not accurately distinguish benign cysts from those that can progress into invasive cancer. Misregulated pericellular proteolysis is a hallmark of malignancy, and therefore, we used a global approach to discover protease activities that differentiate benign nonmucinous cysts from premalignant mucinous cysts.Experimental Design: We employed an unbiased and global protease profiling approach to discover protease activities in 23 cyst fluid samples. The distinguishing activities of select proteases was confirmed in 110 samples using specific fluorogenic substrates and required less than 5 µL of cyst fluid.Results: We determined that the activities of the aspartyl proteases gastricsin and cathepsin E are highly increased in fluid from mucinous cysts. IHC analysis revealed that gastricsin expression was associated with regions of low-grade dysplasia, whereas cathepsin E expression was independent of dysplasia grade. Gastricsin activity differentiated mucinous from nonmucinous cysts with a specificity of 100% and a sensitivity of 93%, whereas cathepsin E activity was 92% specific and 70% sensitive. Gastricsin significantly outperformed the most widely used molecular biomarker, carcinoembryonic antigen (CEA), which demonstrated 94% specificity and 65% sensitivity. Combined analysis of gastricsin and CEA resulted in a near perfect classifier with 100% specificity and 98% sensitivity.Conclusions: Quantitation of gastricsin and cathepsin E activities accurately distinguished mucinous from nonmucinous pancreatic cysts and has the potential to replace current diagnostics for analysis of these highly prevalent lesions. Clin Cancer Res; 23(16); 4865-74. ©2017 AACR.


Assuntos
Líquido Cístico/enzimologia , Cisto Pancreático/enzimologia , Neoplasias Pancreáticas/enzimologia , Peptídeo Hidrolases/metabolismo , Animais , Biomarcadores Tumorais/metabolismo , Antígeno Carcinoembrionário/metabolismo , Catepsina E/metabolismo , Diagnóstico Diferencial , Corantes Fluorescentes/metabolismo , Humanos , Camundongos Knockout , Camundongos Transgênicos , Neoplasias Císticas, Mucinosas e Serosas/diagnóstico , Neoplasias Císticas, Mucinosas e Serosas/enzimologia , Cisto Pancreático/diagnóstico , Neoplasias Pancreáticas/diagnóstico , Pseudocisto Pancreático/diagnóstico , Pseudocisto Pancreático/enzimologia , Pepsina A/metabolismo , Estudos Retrospectivos , Sensibilidade e Especificidade
16.
Cancer Res ; 76(11): 3351-63, 2016 06 01.
Artigo em Inglês | MEDLINE | ID: mdl-27032419

RESUMO

Aberrant regulation of cellular extrusion can promote invasion and metastasis. Here, we identify molecular requirements for early cellular invasion using a premalignant mouse model of pancreatic cancer with conditional knockout of p120 catenin (Ctnnd1). Mice with biallelic loss of p120 catenin progressively develop high-grade pancreatic intraepithelial neoplasia (PanIN) lesions and neoplasia accompanied by prominent acute and chronic inflammatory processes, which is mediated, in part, through NF-κB signaling. Loss of p120 catenin in the context of oncogenic Kras also promotes remarkable apical and basal epithelial cell extrusion. Abundant single epithelial cells exit PanIN epithelium basally, retain epithelial morphology, survive, and display features of malignancy. Similar extrusion defects are observed following p120 catenin knockdown in vitro, and these effects are completely abrogated by the activation of S1P/S1pr2 signaling. In the context of oncogenic Kras, p120 catenin loss significantly reduces expression of genes mediating S1P/S1pr2 signaling in vivo and in vitro, and this effect is mediated at least, in part, through activation of NF-κB. These results provide insight into mechanisms controlling early events in the metastatic process and suggest that p120 catenin and S1P/S1pr2 signaling enhance cancer progression by regulating epithelial cell invasion. Cancer Res; 76(11); 3351-63. ©2016 AACR.


Assuntos
Carcinoma in Situ/patologia , Carcinoma Ductal Pancreático/patologia , Cateninas/metabolismo , Células Epiteliais/patologia , Metaplasia/patologia , Neoplasias Pancreáticas/patologia , Animais , Apoptose , Biomarcadores Tumorais/genética , Biomarcadores Tumorais/metabolismo , Western Blotting , Carcinoma in Situ/genética , Carcinoma in Situ/metabolismo , Carcinoma Ductal Pancreático/genética , Carcinoma Ductal Pancreático/metabolismo , Cateninas/genética , Proliferação de Células , Células Epiteliais/metabolismo , Humanos , Metaplasia/genética , Metaplasia/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , NF-kappa B/genética , NF-kappa B/metabolismo , Invasividade Neoplásica , Estadiamento de Neoplasias , Neoplasias Pancreáticas/genética , Neoplasias Pancreáticas/metabolismo , Prognóstico , RNA Mensageiro/genética , Reação em Cadeia da Polimerase em Tempo Real , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Transdução de Sinais , Células Tumorais Cultivadas , delta Catenina
17.
Nat Med ; 22(5): 497-505, 2016 05.
Artigo em Inglês | MEDLINE | ID: mdl-27089513

RESUMO

Fibrosis compromises pancreatic ductal carcinoma (PDAC) treatment and contributes to patient mortality, yet antistromal therapies are controversial. We found that human PDACs with impaired epithelial transforming growth factor-ß (TGF-ß) signaling have high epithelial STAT3 activity and develop stiff, matricellular-enriched fibrosis associated with high epithelial tension and shorter patient survival. In several KRAS-driven mouse models, both the loss of TGF-ß signaling and elevated ß1-integrin mechanosignaling engaged a positive feedback loop whereby STAT3 signaling promotes tumor progression by increasing matricellular fibrosis and tissue tension. In contrast, epithelial STAT3 ablation attenuated tumor progression by reducing the stromal stiffening and epithelial contractility induced by loss of TGF-ß signaling. In PDAC patient biopsies, higher matricellular protein and activated STAT3 were associated with SMAD4 mutation and shorter survival. The findings implicate epithelial tension and matricellular fibrosis in the aggressiveness of SMAD4 mutant pancreatic tumors and highlight STAT3 and mechanics as key drivers of this phenotype.


Assuntos
Carcinoma Ductal Pancreático/genética , Matriz Extracelular/metabolismo , Cadeias beta de Integrinas/metabolismo , Neoplasias Pancreáticas/genética , Fator de Transcrição STAT3/metabolismo , Fator de Crescimento Transformador beta/metabolismo , Animais , Carcinoma Ductal Pancreático/mortalidade , Carcinoma Ductal Pancreático/patologia , Cromatografia Líquida , Colágeno/metabolismo , Modelos Animais de Doenças , Progressão da Doença , Matriz Extracelular/patologia , Fibrose , Genótipo , Humanos , Camundongos , Microscopia de Força Atômica , Mutação , Neoplasias Pancreáticas/mortalidade , Neoplasias Pancreáticas/patologia , Prognóstico , Proteômica , Proteínas Proto-Oncogênicas p21(ras)/genética , Reação em Cadeia da Polimerase em Tempo Real , Transdução de Sinais , Proteína Smad4/genética , Taxa de Sobrevida , Espectrometria de Massas em Tandem , Microambiente Tumoral
18.
Dev Cell ; 35(6): 674-84, 2015 Dec 21.
Artigo em Inglês | MEDLINE | ID: mdl-26702828

RESUMO

Neoplastic transformation requires changes in cellular identity. Emerging evidence increasingly points to cellular reprogramming, a process during which fully differentiated and functional cells lose aspects of their identity while gaining progenitor characteristics, as a critical early step during cancer initiation. This cell identity crisis persists even at the malignant stage in certain cancers, suggesting that reactivation of progenitor functions supports tumorigenicity. Here, we review recent findings that establish the essential role of cellular reprogramming during neoplastic transformation and the major players involved in it with a special emphasis on pancreatic cancer.


Assuntos
Diferenciação Celular/fisiologia , Transformação Celular Neoplásica/patologia , Reprogramação Celular/genética , Células-Tronco Neoplásicas/patologia , Neoplasias Pancreáticas/patologia , Animais , Linhagem da Célula/fisiologia , Humanos
19.
Sci Rep ; 5: 9841, 2015 Apr 29.
Artigo em Inglês | MEDLINE | ID: mdl-25923013

RESUMO

Metastasis is responsible for over 90% of cancer-associated mortality. In epithelial carcinomas, a key process in metastatic progression is the epigenetic reprogramming of an epithelial-to-mesenchymal transition-like (EMT) change towards invasive cellular phenotypes. In non-epithelial cancers, different mechanisms must underlie metastatic change, but relatively little is known about the factors involved. Here, we identify the chromatin regulatory Sirtuin factor SIRT7 as a key regulator of metastatic phenotypes in both epithelial and mesenchymal cancer cells. In epithelial prostate carcinomas, high SIRT7 levels are associated with aggressive cancer phenotypes, metastatic disease, and poor patient prognosis, and depletion of SIRT7 can reprogram these cells to a less aggressive phenotype. Interestingly, SIRT7 is also important for maintaining the invasiveness and metastatic potential of non-epithelial sarcoma cells. Moreover, SIRT7 inactivation dramatically suppresses cancer cell metastasis in vivo, independent of changes in primary tumor growth. Mechanistically, we also uncover a novel link between SIRT7 and its family member SIRT1, providing the first demonstration of direct interaction and functional interplay between two mammalian sirtuins. Together with previous work, our findings highlight the broad role of SIRT7 in maintaining the metastatic cellular phenotype in diverse cancers.


Assuntos
Células Epiteliais/patologia , Transição Epitelial-Mesenquimal/genética , Metástase Neoplásica/genética , Metástase Neoplásica/patologia , Sarcoma/genética , Sirtuínas/genética , Linhagem Celular Tumoral , Cromatina/genética , Progressão da Doença , Epigênese Genética/genética , Humanos , Fenótipo , Prognóstico , Sarcoma/patologia
20.
Nat Cell Biol ; 16(3): 255-67, 2014 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-24561622

RESUMO

Pancreatic ductal adenocarcinoma (PDA) develops through distinct precursor lesions, including pancreatic intraepithelial neoplasia (PanIN) and intraductal papillary mucinous neoplasia (IPMN). However, genetic features resulting in IPMN-associated PDA (IPMN-PDA) versus PanIN-associated PDA (PanIN-PDA) are largely unknown. Here we find that loss of Brg1, a core subunit of SWI/SNF chromatin remodelling complexes, cooperates with oncogenic Kras to form cystic neoplastic lesions that resemble human IPMN and progress to PDA. Although Brg1-null IPMN-PDA develops rapidly, it possesses a distinct transcriptional profile compared with PanIN-PDA driven by mutant Kras and hemizygous p53 deletion. IPMN-PDA also is less lethal, mirroring prognostic trends in PDA patients. In addition, Brg1 deletion inhibits Kras-dependent PanIN development from adult acinar cells, but promotes Kras-driven preneoplastic transformation in adult duct cells. Therefore, this study implicates Brg1 as a determinant of context-dependent Kras-driven pancreatic tumorigenesis and suggests that chromatin remodelling may underlie the development of distinct PDA subsets.


Assuntos
Adenocarcinoma Mucinoso/metabolismo , Carcinoma Ductal Pancreático/metabolismo , DNA Helicases/fisiologia , Proteínas Nucleares/fisiologia , Neoplasias Pancreáticas/metabolismo , Fatores de Transcrição/fisiologia , Adenocarcinoma Mucinoso/patologia , Animais , Carcinogênese/metabolismo , Carcinogênese/patologia , Carcinoma Ductal Pancreático/patologia , Linhagem Celular Tumoral , Proliferação de Células , Montagem e Desmontagem da Cromatina , Feminino , Humanos , Masculino , Camundongos , Camundongos Endogâmicos NOD , Camundongos SCID , Camundongos Transgênicos , Pâncreas/patologia , Neoplasias Pancreáticas/patologia , Proteínas Proto-Oncogênicas p21(ras)/genética
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