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1.
Cancer Cell ; 42(9): 1614-1629.e5, 2024 Sep 09.
Artigo em Inglês | MEDLINE | ID: mdl-39214094

RESUMO

KRAS mutations in pancreatic ductal adenocarcinoma (PDAC) are suggested to vary in oncogenicity but the implications for human patients have not been explored in depth. We examined 1,360 consecutive PDAC patients undergoing surgical resection and find that KRASG12R mutations are enriched in early-stage (stage I) disease, owing not to smaller tumor size but increased node-negativity. KRASG12R tumors are associated with decreased distant recurrence and improved survival as compared to KRASG12D. To understand the biological underpinnings, we performed spatial profiling of 20 patients and bulk RNA-sequencing of 100 tumors, finding enhanced oncogenic signaling and epithelial-mesenchymal transition (EMT) in KRASG12D and increased nuclear factor κB (NF-κB) signaling in KRASG12R tumors. Orthogonal studies of mouse KrasG12R PDAC organoids show decreased migration and improved survival in orthotopic models. KRAS alterations in PDAC are thus associated with distinct presentation, clinical outcomes, and biological behavior, highlighting the prognostic value of mutational analysis and the importance of articulating mutation-specific PDAC biology.


Assuntos
Carcinoma Ductal Pancreático , Mutação , Neoplasias Pancreáticas , Proteínas Proto-Oncogênicas p21(ras) , Humanos , Proteínas Proto-Oncogênicas p21(ras)/genética , Neoplasias Pancreáticas/genética , Neoplasias Pancreáticas/patologia , Neoplasias Pancreáticas/mortalidade , Carcinoma Ductal Pancreático/genética , Carcinoma Ductal Pancreático/patologia , Carcinoma Ductal Pancreático/mortalidade , Animais , Camundongos , Transição Epitelial-Mesenquimal/genética , Prognóstico , Masculino , Feminino , NF-kappa B/metabolismo , NF-kappa B/genética , Transdução de Sinais/genética , Pessoa de Meia-Idade , Organoides/patologia , Movimento Celular/genética , Idoso
2.
Dev Cell ; 58(24): 2959-2973.e7, 2023 Dec 18.
Artigo em Inglês | MEDLINE | ID: mdl-38056453

RESUMO

Inflammation is essential to the disruption of tissue homeostasis and can destabilize the identity of lineage-committed epithelial cells. Here, we employ lineage-traced mouse models, single-cell transcriptomic and chromatin analyses, and CUT&TAG to identify an epigenetic memory of inflammatory injury in the pancreatic acinar cell compartment. Despite resolution of pancreatitis, our data show that acinar cells fail to return to their molecular baseline, with retention of elevated chromatin accessibility and H3K4me1 at metaplasia genes, such that memory represents an incomplete cell fate decision. In vivo, we find this epigenetic memory controls lineage plasticity, with diminished metaplasia in response to a second insult but increased tumorigenesis with an oncogenic Kras mutation. The lowered threshold for oncogenic transformation, in turn, can be restored by blockade of MAPK signaling. Together, we define the chromatin dynamics, molecular encoding, and recall of a prolonged epigenetic memory of inflammatory injury that impacts future responses but remains reversible.


Assuntos
Carcinoma Ductal Pancreático , Neoplasias Pancreáticas , Camundongos , Animais , Neoplasias Pancreáticas/genética , Neoplasias Pancreáticas/patologia , Memória Epigenética , Transformação Celular Neoplásica/patologia , Células Acinares/patologia , Pâncreas/patologia , Cromatina/genética , Metaplasia/patologia , Carcinoma Ductal Pancreático/genética
3.
Cell Mol Gastroenterol Hepatol ; 13(2): 369-382, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-34352406

RESUMO

The pancreas consists of several specialized cell types that display a remarkable ability to alter cellular identity in injury, regeneration, and repair. The abundant cellular plasticity within the pancreas appears to be exploited in tumorigenesis, with metaplastic, dedifferentiation, and transdifferentiation processes central to the development of pancreatic intraepithelial neoplasia and intraductal papillary neoplasms, precursor lesions to pancreatic ductal adenocarcinoma. In the face of shifting cellular identity, the cell of origin of pancreatic cancer has been difficult to elucidate. However, with the extensive utilization of in vivo lineage-traced mouse models coupled with insights from human samples, it has emerged that the acinar cell is most efficiently able to give rise to both intraductal papillary neoplasms and pancreatic intraepithelial neoplasia but that acinar and ductal cells can undergo malignant transformation to pancreatic ductal adenocarcinoma. In this review, we discuss the cellular reprogramming that takes place in both the normal and malignant pancreas and evaluate the current state of evidence that implicate both the acinar and ductal cell as context-dependent origins of this deadly disease.


Assuntos
Carcinoma Ductal Pancreático , Neoplasias Pancreáticas , Células Acinares/patologia , Animais , Carcinoma Ductal Pancreático/patologia , Plasticidade Celular , Camundongos , Pâncreas/patologia , Neoplasias Pancreáticas/patologia
4.
J Virol ; 95(23): e0125721, 2021 11 09.
Artigo em Inglês | MEDLINE | ID: mdl-34523966

RESUMO

SARS-CoV-2, the etiological agent of COVID-19, is characterized by a delay in type I interferon (IFN-I)-mediated antiviral defenses alongside robust cytokine production. Here, we investigate the underlying molecular basis for this imbalance and implicate virus-mediated activation of NF-κB in the absence of other canonical IFN-I-related transcription factors. Epigenetic and single-cell transcriptomic analyses show a selective NF-κB signature that was most prominent in infected cells. Disruption of NF-κB signaling through the silencing of the NF-κB transcription factor p65 or p50 resulted in loss of virus replication that was rescued upon reconstitution. These findings could be further corroborated with the use of NF-κB inhibitors, which reduced SARS-CoV-2 replication in vitro. These data suggest that the robust cytokine production in response to SARS-CoV-2, despite a diminished IFN-I response, is the product of a dependency on NF-κB for viral replication. IMPORTANCE The COVID-19 pandemic has caused significant mortality and morbidity around the world. Although effective vaccines have been developed, large parts of the world remain unvaccinated while new SARS-CoV-2 variants keep emerging. Furthermore, despite extensive efforts and large-scale drug screenings, no fully effective antiviral treatment options have been discovered yet. Therefore, it is of the utmost importance to gain a better understanding of essential factors driving SARS-CoV-2 replication to be able to develop novel approaches to target SARS-CoV-2 biology.


Assuntos
COVID-19/metabolismo , Citocinas/metabolismo , Interferon Tipo I/metabolismo , SARS-CoV-2 , Fator de Transcrição RelA/metabolismo , Transcriptoma , Replicação Viral , Células A549 , Animais , COVID-19/virologia , Chlorocebus aethiops , Epigenômica , Regulação da Expressão Gênica , Células HEK293 , Células HeLa , Interações entre Hospedeiro e Microrganismos , Humanos , Transdução de Sinais , Análise de Célula Única , Fator de Transcrição RelA/antagonistas & inibidores , Fator de Transcrição RelA/genética , Fatores de Transcrição/metabolismo , Células Vero
5.
Cancer Res ; 77(8): 1868-1879, 2017 04 15.
Artigo em Inglês | MEDLINE | ID: mdl-28386018

RESUMO

Nerves are a notable feature of the tumor microenvironment in some epithelial tumors, but their role in the malignant progression of pancreatic ductal adenocarcinoma (PDAC) is uncertain. Here, we identify dense innervation in the microenvironment of precancerous pancreatic lesions, known as pancreatic intraepithelial neoplasms (PanIN), and describe a unique subpopulation of neuroendocrine PanIN cells that express the neuropeptide substance P (SP) receptor neurokinin 1-R (NK1-R). Using organoid culture, we demonstrated that sensory neurons promoted the proliferation of PanIN organoids via SP-NK1-R signaling and STAT3 activation. Nerve-responsive neuroendocrine cells exerted trophic influences and potentiated global PanIN organoid growth. Sensory denervation of a genetically engineered mouse model of PDAC led to loss of STAT3 activation, a decrease in the neoplastic neuroendocrine cell population, and impaired PanIN progression to tumor. Overall, our data provide evidence that nerves of the PanIN microenvironment promote oncogenesis, likely via direct signaling to neoplastic neuroendocrine cells capable of trophic influences. These findings identify neuroepithelial cross-talk as a potential novel target in PDAC treatment. Cancer Res; 77(8); 1868-79. ©2017 AACR.


Assuntos
Carcinoma Ductal Pancreático/patologia , Células Neuroendócrinas/patologia , Pâncreas/inervação , Neoplasias Pancreáticas/patologia , Lesões Pré-Cancerosas/patologia , Células Receptoras Sensoriais/patologia , Células 3T3 , Animais , Carcinogênese , Modelos Animais de Doenças , Gânglios Espinais/patologia , Células HEK293 , Humanos , Camundongos , Camundongos Endogâmicos C57BL , Células Neuroendócrinas/metabolismo , Pâncreas/patologia , Fator de Transcrição STAT3/metabolismo , Células Receptoras Sensoriais/metabolismo , Substância P/biossíntese
6.
Gut ; 64(11): 1790-9, 2015 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-25336113

RESUMO

OBJECTIVE: The transcription factor SOX9 was recently shown to stimulate ductal gene expression in pancreatic acinar-to-ductal metaplasia and to accelerate development of premalignant lesions preceding pancreatic ductal adenocarcinoma (PDAC). Here, we investigate how SOX9 operates in pancreatic tumourigenesis. DESIGN: We analysed genomic and transcriptomic data from surgically resected PDAC and extended the expression analysis to xenografts from PDAC samples and to PDAC cell lines. SOX9 expression was manipulated in human cell lines and mouse models developing PDAC. RESULTS: We found genetic aberrations in the SOX9 gene in about 15% of patient tumours. Most PDAC samples strongly express SOX9 protein, and SOX9 levels are higher in classical PDAC. This tumour subtype is associated with better patient outcome, and cell lines of this subtype respond to therapy targeting epidermal growth factor receptor (EGFR/ERBB1) signalling, a pathway essential for pancreatic tumourigenesis. In human PDAC, high expression of SOX9 correlates with expression of genes belonging to the ERBB pathway. In particular, ERBB2 expression in PDAC cell lines is stimulated by SOX9. Inactivating Sox9 expression in mice confirmed its role in PDAC initiation; it demonstrated that Sox9 stimulates expression of several members of the ERBB pathway and is required for ERBB signalling activity. CONCLUSIONS: By integrating data from patient samples and mouse models, we found that SOX9 regulates the ERBB pathway throughout pancreatic tumourigenesis. Our work opens perspectives for therapy targeting tumourigenic mechanisms.


Assuntos
Adenocarcinoma/etiologia , Carcinoma Ductal Pancreático/etiologia , Receptores ErbB/fisiologia , Neoplasias Pancreáticas/etiologia , Fatores de Transcrição SOX9/fisiologia , Adenocarcinoma/genética , Animais , Carcinoma Ductal Pancreático/genética , Transformação Celular Neoplásica , Regulação Neoplásica da Expressão Gênica , Humanos , Camundongos , Neoplasias Pancreáticas/genética , Fatores de Transcrição SOX9/genética , Transdução de Sinais
7.
Gut ; 61(12): 1723-32, 2012 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-22271799

RESUMO

OBJECTIVE: Growing evidence suggests that a phenotypic switch converting pancreatic acinar cells to duct-like cells can lead to pancreatic intraepithelial neoplasia and eventually to invasive pancreatic ductal adenocarcinoma. Histologically, the onset of this switch is characterised by the co-expression of acinar and ductal markers in acini, a lesion called acinar-to-ductal metaplasia (ADM). The transcriptional regulators required to initiate ADM are unknown, but need to be identified to characterise the regulatory networks that drive ADM. In this study, the role of the ductal transcription factors hepatocyte nuclear factor 6 (HNF6, also known as Onecut1) and SRY-related HMG box factor 9 (Sox9) in ADM was investigated. DESIGN: Expression of HNF6 and Sox9 was measured by immunostaining in normal and diseased human pancreas. The function of the factors was tested in cultured cells and in mouse models of ADM by a combination of gain and loss of function experiments. RESULTS: Expression of HNF6 and Sox9 was ectopically induced in acinar cells in human ADM as well as in mouse models of ADM. HNF6 and, to a lesser extent, Sox9 were required for repression of acinar genes, for modulation of ADM-associated changes in cell polarity and for activation of ductal genes in metaplastic acinar cells. CONCLUSIONS: HNF6 and Sox9 are new biomarkers of ADM and constitute candidate targets for preventive treatment in cases when ADM may lead to cancer. This work also shows that ectopic activation of transcription factors may underlie metaplastic processes occurring in other organs.


Assuntos
Células Acinares/patologia , Biomarcadores Tumorais/metabolismo , Transformação Celular Neoplásica/metabolismo , Fator 6 Nuclear de Hepatócito/metabolismo , Pâncreas/patologia , Fatores de Transcrição SOX9/metabolismo , Células Acinares/metabolismo , Animais , Western Blotting , Células Cultivadas , Cobaias , Humanos , Metaplasia , Camundongos , Modelos Animais , Pâncreas/metabolismo , Reação em Cadeia da Polimerase em Tempo Real , Reação em Cadeia da Polimerase Via Transcriptase Reversa
8.
FEBS Lett ; 583(10): 1644-8, 2009 May 19.
Artigo em Inglês | MEDLINE | ID: mdl-19401201

RESUMO

Renal functions are regulated by steroid sex hormones, but the exhaustive identification of their receptors along the nephron is still lacking. Here, we have localized all known nuclear or membrane-bound sex hormone receptors and some of their activators along the nephron of male and female mice. Almost all receptors are present in male and female kidney, some of them having very restricted localization. Only one gene tested among 11 (ARA54) exhibits a gender difference in the level of its expression. This first "renal map" of sex steroid receptor expression may serve as a pre-requisite for investigating the role of these hormones on kidney functions.


Assuntos
Néfrons/metabolismo , Receptores de Esteroides/metabolismo , Animais , Feminino , Hormônios Esteroides Gonadais/metabolismo , Rim/metabolismo , Masculino , Camundongos , RNA Mensageiro/metabolismo , Receptores de Esteroides/análise
9.
Biochim Biophys Acta ; 1783(12): 2234-40, 2008 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-18722485

RESUMO

Sex hormones have broader effects than regulating reproductive functions. Recent identification of membrane progestin receptors expressed in kidney prompted us to investigate their putative involvement in the renal effects of this hormone. We first focused our investigations on mPRalpha and gamma by analyzing three parameters 1/ their distribution along the mouse nephron and their subcellular location in native kidney, 2/ the ability of progesterone to stimulate ERK pathway and/or Ca(2+) release from internal stores in native kidney structures and 3/ the cellular localization of mPRalpha and its molecular determinants in heterologous expression system. We observed that 1/ mPRalpha expression is restricted to proximal tubules of both male and female mice whereas mPRgamma exhibits a much broader expression all along the nephron except the glomerulus, 2/ mPRalpha and gamma are not localized at the plasma membrane in native kidney, 3/ this expression does not permit either progesterone-induced ERK phosphorylation or Ca(2+) release and 4/ in HEK transfected cells, mPRalpha localizes in the endoplasmic reticulum (ER) due to a C-terminal ER retention motif (-KXX). Therefore, we have characterized mPRs in kidney but their role in renal physiology remains to be elucidated.


Assuntos
Membrana Celular/metabolismo , Túbulos Renais Proximais/metabolismo , Progesterona/metabolismo , Receptores Acoplados a Proteínas G/metabolismo , Receptores de Progesterona/metabolismo , Animais , Western Blotting , Cálcio/metabolismo , Células Cultivadas , Retículo Endoplasmático/metabolismo , Feminino , Humanos , Técnicas Imunoenzimáticas , Rim/metabolismo , Túbulos Renais Proximais/citologia , Masculino , Camundongos , Proteína Quinase 1 Ativada por Mitógeno/metabolismo , Proteína Quinase 3 Ativada por Mitógeno/metabolismo , Fragmentos de Peptídeos , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Receptores Acoplados a Proteínas G/genética , Receptores de Progesterona/genética , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Transdução de Sinais , Frações Subcelulares , Ácidos Tri-Iodobenzoicos/farmacologia
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