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1.
Anticancer Res ; 40(10): 5765-5776, 2020 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-32988904

RESUMO

BACKGROUND/AIM: We evaluated the safety, feasibility, and preliminary efficacy of Wilms tumor gene 1 (WT1) peptide and Mucin 1 (MUC1)-pulsed dendritic cell (DC) (WT1/MUC1-DC) vaccination as an adjuvant immunotherapy for surgically resectable pancreatic ductal adenocarcinoma (PDA) patients. PATIENTS AND METHODS: Eligible patients were administered WT1/MUC1-DC vaccination at least seven times every 2 weeks with concomitant adjuvant chemotherapy after surgical resection of PDA. RESULTS: Ten patients were enrolled and no Grade 2 or higher toxicities were associated with DC vaccination. The estimated overall survival (OS) and relapse-free survival (RFS) at 3-years from the time of surgical resection were 77.8% and 35.0%, respectively. Immunohistochemical analysis suggested a possible relationship between induction of WT1-specific cytotoxic T lymphocyte after DC vaccination and higher infiltration of CD3/CD4/CD8 lymphocytes in tumor tissues. CONCLUSION: WT1/MUC1-DC vaccination in the adjuvant setting was safe and well-tolerated in PDA patients after tumor resection. A large-scale prospective study is warranted to evaluate the clinical benefit of this modality.


Assuntos
Adenocarcinoma/tratamento farmacológico , Carcinoma Ductal Pancreático/tratamento farmacológico , Mucina-1/genética , Proteínas WT1/genética , Adenocarcinoma/genética , Adenocarcinoma/patologia , Adenocarcinoma/cirurgia , Idoso , Vacinas Anticâncer/administração & dosagem , Vacinas Anticâncer/imunologia , Carcinoma Ductal Pancreático/genética , Carcinoma Ductal Pancreático/patologia , Carcinoma Ductal Pancreático/cirurgia , Quimioterapia Adjuvante/métodos , Células Dendríticas/imunologia , Desoxicitidina/administração & dosagem , Desoxicitidina/análogos & derivados , Intervalo Livre de Doença , Feminino , Humanos , Imunoterapia/métodos , Masculino , Pessoa de Meia-Idade , Mucina-1/uso terapêutico , Proteínas WT1/uso terapêutico
2.
Nat Commun ; 11(1): 4516, 2020 09 09.
Artigo em Inglês | MEDLINE | ID: mdl-32908137

RESUMO

Acinar metaplasia is an initial step in a series of events that can lead to pancreatic cancer. Here we perform single-cell RNA-sequencing of mouse pancreas during the progression from preinvasive stages to tumor formation. Using a reporter gene, we identify metaplastic cells that originated from acinar cells and express two transcription factors, Onecut2 and Foxq1. Further analyses of metaplastic acinar cell heterogeneity define six acinar metaplastic cell types and states, including stomach-specific cell types. Localization of metaplastic cell types and mixture of different metaplastic cell types in the same pre-malignant lesion is shown. Finally, single-cell transcriptome analyses of tumor-associated stromal, immune, endothelial and fibroblast cells identify signals that may support tumor development, as well as the recruitment and education of immune cells. Our findings are consistent with the early, premalignant formation of an immunosuppressive environment mediated by interactions between acinar metaplastic cells and other cells in the microenvironment.


Assuntos
Células Acinares/patologia , Carcinoma Ductal Pancreático/genética , Regulação Neoplásica da Expressão Gênica , Pâncreas/patologia , Neoplasias Pancreáticas/genética , Lesões Pré-Cancerosas/genética , Animais , Animais Geneticamente Modificados , Biópsia , Carcinoma Ductal Pancreático/mortalidade , Carcinoma Ductal Pancreático/patologia , Carcinoma Ductal Pancreático/cirurgia , Diferenciação Celular , Modelos Animais de Doenças , Feminino , Fatores de Transcrição Forkhead/genética , Fatores de Transcrição Forkhead/metabolismo , Heterogeneidade Genética , Proteínas de Homeodomínio/genética , Proteínas de Homeodomínio/metabolismo , Humanos , Estimativa de Kaplan-Meier , Masculino , Metaplasia/genética , Camundongos , Mutação , Pâncreas/citologia , Pâncreas/cirurgia , Pancreatectomia , Neoplasias Pancreáticas/mortalidade , Neoplasias Pancreáticas/patologia , Neoplasias Pancreáticas/cirurgia , Lesões Pré-Cancerosas/patologia , Proteínas Proto-Oncogênicas p21(ras)/genética , RNA-Seq , Análise de Célula Única , Fatores de Transcrição/genética , Fatores de Transcrição/metabolismo , Microambiente Tumoral/genética
3.
Ann Surg ; 272(2): 366-376, 2020 08.
Artigo em Inglês | MEDLINE | ID: mdl-32675551

RESUMO

OBJECTIVE: We aimed to define preoperative clinical and molecular characteristics that would allow better patient selection for operative resection. BACKGROUND: Although we use molecular selection methods for systemic targeted therapies, these principles are not applied to surgical oncology. Improving patient selection is of vital importance for the operative treatment of pancreatic cancer (pancreatic ductal adenocarcinoma). Although surgery is the only chance of long-term survival, 80% still succumb to the disease and approximately 30% die within 1 year, often sooner than those that have unresected local disease. METHOD: In 3 independent pancreatic ductal adenocarcinoma cohorts (total participants = 1184) the relationship between aberrant expression of prometastatic proteins S100A2 and S100A4 and survival was assessed. A preoperative nomogram based on clinical variables available before surgery and expression of these proteins was constructed and compared to traditional measures, and a postoperative nomogram. RESULTS: High expression of either S100A2 or S100A4 was independent poor prognostic factors in a training cohort of 518 participants. These results were validated in 2 independent patient cohorts (Glasgow, n = 198; Germany, n = 468). Aberrant biomarker expression stratified the cohorts into 3 distinct prognostic groups. A preoperative nomogram incorporating S100A2 and S100A4 expression predicted survival and nomograms derived using postoperative clinicopathological variables. CONCLUSIONS: Of those patients with a poor preoperative nomogram score, approximately 50% of patients died within a year of resection. Nomograms have the potential to improve selection for surgery and neoadjuvant therapy, avoiding surgery in aggressive disease, and justifying more extensive resections in biologically favorable disease.


Assuntos
Carcinoma Ductal Pancreático/genética , Carcinoma Ductal Pancreático/mortalidade , Fatores Quimiotáticos/genética , Pancreatectomia/métodos , Neoplasias Pancreáticas/genética , Neoplasias Pancreáticas/mortalidade , Proteínas S100/genética , Idoso , Carcinoma Ductal Pancreático/cirurgia , Causas de Morte , Estudos de Coortes , Intervalo Livre de Doença , Feminino , Regulação Neoplásica da Expressão Gênica , Humanos , Masculino , Pessoa de Meia-Idade , Nomogramas , Pancreatectomia/mortalidade , Neoplasias Pancreáticas/cirurgia , Seleção de Pacientes , Prognóstico , Modelos de Riscos Proporcionais , Estudos Retrospectivos , Medição de Risco , Análise de Sobrevida
4.
Nat Commun ; 11(1): 3303, 2020 07 03.
Artigo em Inglês | MEDLINE | ID: mdl-32620742

RESUMO

Pancreatic ductal adenocarcinoma (PDAC) lethality is due to metastatic dissemination. Characterization of rare, heterogeneous circulating tumor cells (CTCs) can provide insight into metastasis and guide development of novel therapies. Using the CTC-iChip to purify CTCs from PDAC patients for RNA-seq characterization, we identify three major correlated gene sets, with stemness genes LIN28B/KLF4, WNT5A, and LGALS3 enriched in each correlated gene set; only LIN28B CTC expression was prognostic. CRISPR knockout of LIN28B-an oncofetal RNA-binding protein exerting diverse effects via negative regulation of let-7 miRNAs and other RNA targets-in cell and animal models confers a less aggressive/metastatic phenotype. This correlates with de-repression of let-7 miRNAs and is mimicked by silencing of downstream let-7 target HMGA2 or chemical inhibition of LIN28B/let-7 binding. Molecular characterization of CTCs provides a unique opportunity to correlated gene set metastatic profiles, identify drivers of dissemination, and develop therapies targeting the "seeds" of metastasis.


Assuntos
Carcinoma Ductal Pancreático/genética , Proteína HMGA2/genética , MicroRNAs/genética , Células Neoplásicas Circulantes/metabolismo , Neoplasias Pancreáticas/genética , Proteínas de Ligação a RNA/genética , Adulto , Idoso , Animais , Carcinoma Ductal Pancreático/tratamento farmacológico , Carcinoma Ductal Pancreático/metabolismo , Linhagem Celular Tumoral , Movimento Celular/genética , Feminino , Regulação Neoplásica da Expressão Gênica , Proteína HMGA2/metabolismo , Humanos , Estimativa de Kaplan-Meier , Masculino , Camundongos Endogâmicos NOD , Camundongos Knockout , Camundongos SCID , Pessoa de Meia-Idade , Metástase Neoplásica , Neoplasias Pancreáticas/tratamento farmacológico , Neoplasias Pancreáticas/metabolismo , Proteínas de Ligação a RNA/metabolismo
5.
Nat Commun ; 11(1): 3409, 2020 07 08.
Artigo em Inglês | MEDLINE | ID: mdl-32641778

RESUMO

Pancreatic ductal adenocarcinoma (PDAC) is associated with high mortality and therapy resistance. Here, we show that low expression of κB-Ras GTPases is frequently detected in PDAC and correlates with higher histologic grade. In a model of KRasG12D-driven PDAC, loss of κB-Ras accelerates tumour development and shortens median survival. κB-Ras deficiency promotes acinar-to-ductal metaplasia (ADM) during tumour initiation as well as tumour progression through intrinsic effects on proliferation and invasion. κB-Ras proteins are also required for acinar regeneration after pancreatitis, demonstrating a general role in control of plasticity. Molecularly, upregulation of Ral GTPase activity and Sox9 expression underlies the observed phenotypes, identifying a previously unrecognized function of Ral signalling in ADM. Our results provide evidence for a tumour suppressive role of κB-Ras proteins and highlight low κB-Ras levels and consequent loss of Ral control as risk factors, thus emphasizing the necessity for therapeutic options that allow interference with Ral-driven signalling.


Assuntos
Células Acinares/metabolismo , Carcinoma Ductal Pancreático/genética , GTP Fosfo-Hidrolases/genética , Neoplasias Pancreáticas/genética , Pancreatite/genética , Proteínas/genética , Células Acinares/patologia , Idoso , Animais , Carcinoma Ductal Pancreático/metabolismo , Carcinoma Ductal Pancreático/patologia , Linhagem Celular Tumoral , Feminino , GTP Fosfo-Hidrolases/metabolismo , Regulação da Expressão Gênica , Humanos , Proteínas I-kappa B/genética , Proteínas I-kappa B/metabolismo , Estimativa de Kaplan-Meier , Masculino , Metaplasia/genética , Metaplasia/metabolismo , Camundongos Endogâmicos C57BL , Camundongos Knockout , Pessoa de Meia-Idade , Neoplasias Pancreáticas/metabolismo , Neoplasias Pancreáticas/patologia , Pancreatite/metabolismo , Proteínas/metabolismo , Fatores de Transcrição SOX9/genética , Fatores de Transcrição SOX9/metabolismo , Proteínas ral de Ligação ao GTP/genética , Proteínas ral de Ligação ao GTP/metabolismo , Proteínas ras/genética , Proteínas ras/metabolismo
6.
Gene ; 758: 144960, 2020 Oct 20.
Artigo em Inglês | MEDLINE | ID: mdl-32687947

RESUMO

As a member of the ubiquitin-specific protease (USP) family, USP22 could remove ubiquitin moieties from its target proteins to control the function of the target proteins. Accumulating studies show that USP22 essentially participates in diverse types of cancer as an oncogene-like protein. However, the roles of USP22 in human pancreatic ductal adenocarcinoma (PDAC) and the underlying mechanism are unknown. Here we report that USP22 promotes the growth of PDAC cells by promoting the expression of dual-specificity tyrosine regulated kinase 1A (DYRK1A). Our results showed that the expression levels of USP22 were up-regulated in human PDAC tissues and cell lines (BxPC-3, AsPC-1, MIA-PaCa-2, PANC-1, and CAPAN-1). Lentivirus-mediated knockdown of USP22 repressed the rate of proliferation and capacity of colony formation of BxPC3 and CAPAN1 cancer cells and USP22 overexpression promoted the proliferation and capacity of the colony formation of BxPC3 and CAPAN1 cancer cells. The further mechanism study showed that USP22 elevated the expression of the mRNA and protein levels of DYRK1A in PDAC cancer cells. Inhibition of DYRK1A with EHT-5732 or lentivirus-mediated knockdown of DYRK1A blocked the function of USP22 overexpression in the regulation of the proliferation and colony formation of PDAC cells. Taken together, our findings demonstrated that USP22 overexpression in PDAC promoted the growth of the cancer cells partially through upregulating the expression of DYRK1A.


Assuntos
Carcinoma Ductal Pancreático/genética , Neoplasias Pancreáticas/genética , Proteínas Serina-Treonina Quinases/metabolismo , Proteínas Tirosina Quinases/metabolismo , Ubiquitina Tiolesterase/genética , Animais , Apoptose/genética , Linhagem Celular Tumoral , Proliferação de Células/genética , Regulação Neoplásica da Expressão Gênica , Humanos , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Nus , Transplante de Neoplasias , Oncogenes/genética , Ductos Pancreáticos/patologia , RNA Mensageiro/genética , Transplante Heterólogo
7.
Anticancer Res ; 40(8): 4401-4404, 2020 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-32727769

RESUMO

BACKGROUND: The occurrence of lung adenocarcinoma metastasizing to the pancreas is overall rare and can histologically imitate primary pancreatic ductal carcinoma (PDAC). CASE REPORT: This is a case report of a 70-year-old female with a history of surgically resected right lung adenocarcinoma presenting for routine follow up without symptoms. CT scans revealed a pancreatic cystic mass with ductal dilatation that was sampled via endoscopic ultrasound-guided fine needle aspiration (EUS-FNA) and thought to be a primary pancreatic mucinous neoplasm with high grade dysplasia suspicious for carcinoma based on smear cytology. On repeat EUS-FNA and biopsy (FNB) with additional immunohistochemical testing for lung adenocarcinoma markers thyroid transcription factor (TTF1) and Napsin A and molecular testing, the lesion was identified as a metastasis of lung adenocarcinoma with an epidermal growth factor receptor (EGFR L858R) mutation; subsequently, the patient underwent targeted therapy that yielded an almost complete response. CONCLUSION: To the best of our knowledge, this is the first documented case in English literature of a lung adenocarcinoma metastasis to the pancreas mimicking a pancreatic primary neoplasm and highlights the potential pitfalls of EUS-FNA for the diagnosis of certain metastases to the pancreas.


Assuntos
Adenocarcinoma de Pulmão/diagnóstico por imagem , Neoplasias Pulmonares/diagnóstico por imagem , Neoplasias Pancreáticas/secundário , Adenocarcinoma de Pulmão/genética , Adenocarcinoma de Pulmão/metabolismo , Adenocarcinoma de Pulmão/patologia , Idoso , Biomarcadores/metabolismo , Carcinoma Ductal Pancreático/diagnóstico por imagem , Carcinoma Ductal Pancreático/genética , Carcinoma Ductal Pancreático/metabolismo , Carcinoma Ductal Pancreático/patologia , Diagnóstico Diferencial , Aspiração por Agulha Fina Guiada por Ultrassom Endoscópico , Receptores ErbB/genética , Feminino , Humanos , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/metabolismo , Neoplasias Pulmonares/patologia , Mutação , Neoplasias Pancreáticas/genética , Neoplasias Pancreáticas/metabolismo , Neoplasias Pancreáticas/patologia , Tomografia Computadorizada por Raios X
8.
Anticancer Res ; 40(8): 4445-4455, 2020 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-32727774

RESUMO

BACKGROUND/AIM: To examine interferon (IFN) signaling pathways in human pancreatic cancer cells and their therapeutic application for pancreatic ductal adenocarcinoma (PDAC). MATERIALS AND METHODS: We examined the effects of IFNα on cytotoxicity, migration, as well as on the levels of toll-like receptor (TLR) signaling pathway-associated genes expression in pancreatic cancer cells. We also examined the additive effects of IFNα and poly(I-C) on tyrosine kinase inhibitor (TKI)-induced cytotoxicity. We performed transcriptome analysis (RNA-Seq) of clinical samples and compared the profile between pancreatic intraepithelial neoplasias (PanINs) and PDACs. RESULTS: IFNα suppressed cell viability and cell migration, and affected TLR signaling pathways, in pancreatic cancer cells. TLR3 is one of the potential genes involved in IFN-treated pancreatic cancer cells. Furthermore, similar to IFN, extracellular addition of poly(I-C) enhanced TKI-induced cytotoxicity in pancreatic cancer cells. RNA-Seq analysis demonstrated that IFN signaling is one of the potential pathways involved in the progression of PanIN to PDAC. CONCLUSION: IFN signaling may be involved in the development of PDAC. Treatments that target the IFN and TLR3 signaling pathways may be therapeutic options against PDAC.


Assuntos
Carcinoma in Situ/genética , Carcinoma Ductal Pancreático/genética , Perfilação da Expressão Gênica/métodos , Interferons/metabolismo , Neoplasias Pancreáticas/genética , Poli I-C/farmacologia , Receptores Toll-Like/genética , Idoso , Carcinoma in Situ/tratamento farmacológico , Carcinoma in Situ/metabolismo , Carcinoma Ductal Pancreático/tratamento farmacológico , Carcinoma Ductal Pancreático/metabolismo , Linhagem Celular Tumoral , Movimento Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Progressão da Doença , Feminino , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Humanos , Masculino , Pessoa de Meia-Idade , Neoplasias Pancreáticas/tratamento farmacológico , Neoplasias Pancreáticas/metabolismo , Inibidores de Proteínas Quinases/farmacologia , Análise de Sequência de RNA , Transdução de Sinais/efeitos dos fármacos
9.
Cancer Treat Rev ; 87: 102028, 2020 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-32485509

RESUMO

While no biomarker is currently recommended for the management of pancreatic adenocarcinoma (PA), circulating tumor DNA (ctDNA) seems promising but little is known on how it may help to manage our patients in the near future. This systematic review of literature was designed to explore the current knowledge on ctDNA as a screening, diagnostic, prognostic, predictive and theranostic biomarker in the management of PA. We retrieved 62 full-text articles, 3 meta-analyses, 2 clinical trials, 1 abstract and 13 ongoing trials. Results were categorized into sections about screening, diagnosis, prognosis and follow-up of localized and advanced PA together with possible theranostics applications. Although its specificity is excellent, the current sensitivity of ctDNA remains a limitation especially in patients without metastatic disease. Therefore, this biomarker cannot be currently used as a screening or diagnostic tool. Increasing evidence suggests that ctDNA is a relevant candidate biomarker to assess minimal residual disease after radical surgery, but also a strong independent biomarker linked to a poor prognosis in advanced PA. Some recent data also indicates that ctDNA is an attractive biomarker for longitudinal follow-up and possibly early treatment adaptation. Its role in tumor profiling in advanced disease to decide targeted treatments remains to be explored. Altogether, ctDNA appears to be a reliable prognostic tool. Though promising results have been reported, further studies are still needed to define exactly how ctDNA can help physicians in the screening, diagnosis and treatment, as PA is expected to become a major cause of cancer-related deaths in the forthcoming decade.


Assuntos
Carcinoma Ductal Pancreático/diagnóstico , Carcinoma Ductal Pancreático/terapia , DNA Tumoral Circulante/sangue , Neoplasias Pancreáticas/diagnóstico , Neoplasias Pancreáticas/terapia , Biomarcadores Tumorais/sangue , Biomarcadores Tumorais/genética , Carcinoma Ductal Pancreático/sangue , Carcinoma Ductal Pancreático/genética , DNA Tumoral Circulante/genética , Seguimentos , Humanos , Neoplasias Pancreáticas/sangue , Neoplasias Pancreáticas/genética , Prognóstico
10.
Anticancer Res ; 40(6): 3109-3118, 2020 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-32487605

RESUMO

BACKGROUND/AIM: Pancreatic cancer is one of the deadliest forms of cancer and ranks among the leading causes of cancer-related death worldwide. The most common histological type is ductal adenocarcinoma (PDAC), accounting for approximately 95% of cases. Deregulation of protein synthesis has been found to be closely related to cancer. The rate-limiting step of translation is initiation, which is regulated by a broad range of eukaryotic translation initiation factors (eIFs). PATIENTS AND METHODS: Human PDAC samples were biochemically analyzed for the expression of various eIF subunits on the protein level (immunohistochemistry, immunoblot analyses) in 174 cases of PDAC in comparison with non-neoplastic pancreatic tissue (n=10). RESULTS: Our investigation revealed a significant down-regulation of four specific eIF subunits, namely eIF1, eIF2D, eIF3C and eIF6. Concomitantly, the protein (immunoblot) levels of eIF1, eIF2D, eIF3C and eIF6 were reduced in PDAC samples as compared with non-neoplastic pancreatic tissue. CONCLUSION: Members of the eIF family are of relevance in pancreatic tumor biology and may play a major role in translational control in PDAC. Consequently, they might be useful as potential new biomarkers and therapeutic targets in PDAC.


Assuntos
Biomarcadores Tumorais/genética , Carcinoma Ductal Pancreático/genética , Fatores de Iniciação em Eucariotos/genética , Neoplasias Pancreáticas/genética , Biomarcadores Tumorais/metabolismo , Carcinoma Ductal Pancreático/metabolismo , Carcinoma Ductal Pancreático/patologia , Regulação para Baixo , Fatores de Iniciação em Eucariotos/biossíntese , Fatores de Iniciação em Eucariotos/metabolismo , Humanos , Imuno-Histoquímica , Neoplasias Pancreáticas/metabolismo , Fosfatidilinositol 3-Quinases/metabolismo , Proteínas Proto-Oncogênicas c-akt/metabolismo , Transdução de Sinais , Taxa de Sobrevida , Serina-Treonina Quinases TOR/metabolismo , Análise Serial de Tecidos
11.
Medicine (Baltimore) ; 99(26): e20950, 2020 Jun 26.
Artigo em Inglês | MEDLINE | ID: mdl-32590806

RESUMO

BACKGROUND: Glioma-associated oncogene homolog 1(GLI1) expression correlates with the clinical significance and prognosis of several cancers. However, the evaluation of the role GLI1 expression plays in pancreatic ductal adenocarcinoma (PDAC) clinicopathological features and outcomes still lacks. OBJECTIVE: The present study systemic reviewed the association of GLI1 expression and clinical significance as well as patients survival in PDAC. METHODS: We systematically searched the database of The Cochrane Library, PubMed, Embase, CNKI, Weipu data, and Wanfang data according to the inclusion and exclusion criteria. (The search ended on January 1, 2019; no language restrictions). The Newcastle-Ottawa Scale (NOS) scale was implemented to assess the quality of the literature and the Review Manager 5.3 Software was used to conduct a meta-analysis. Finally, 9 studies, a total of 1058 patients, have been included. RESULTS: GLI1 is more likely expressed in PDAC tissue rather than para-carcinoma tissue (OR = 2.86, 95%CI = 1.87-4.36, P < .00001). GLI1 expression is associated with the TNM stage (OR = 3.11, 95%CI = 2.01-4.79, P < .00001), perineural invasion (OR = 2.50, 95%CI = 1.28-4.91, P = .008), and lymphatic metastasis (OR = 2.73, 95%CI = 1.71-4.36, P < .0001). But the association with differentiation (OR = 1.20, 95%CI = 0.74-1.96, P = .46) and tumor size (OR = 2.41, 95%CI = 0.97-6.00, P = .06) was not significant. GLI1 expression is related to the worse overall survival in PDACs (HR = 1.68, 95%CI = 1.40-2.02, P < .00001). CONCLUSION: Positive GLI1 expression promotes the progression and metastasis of PDACs and plays an important role in the clinical significance and the patients survival.


Assuntos
Carcinoma Ductal Pancreático/enzimologia , Prognóstico , Proteína GLI1 em Dedos de Zinco/análise , Adenocarcinoma/enzimologia , Adenocarcinoma/genética , Biomarcadores Tumorais/análise , Biomarcadores Tumorais/sangue , Carcinoma Ductal Pancreático/genética , Humanos
12.
Medicine (Baltimore) ; 99(25): e20564, 2020 Jun 19.
Artigo em Inglês | MEDLINE | ID: mdl-32569179

RESUMO

INTRODUCTION: Surgical management is not a standard treatment option for metastatic recurrence of pancreatic adenocarcinoma. However, the surgical management of a solitary metastasis is useful in selected cases. PATIENT CONCERNS: A 42-year-old woman was referred to our hospital on account of epigastric pain associated with a mass in the pancreatic body. The patient had a family history of branch duct-type intraductal papillary mucinous neoplasm of the pancreas. DIAGNOSIS: The patient was diagnosed with pancreatic ductal adenocarcinoma (PDA) complicated with pancreatitis due to pancreatic duct involvement. INTERVENTIONS: The patient underwent distal pancreatectomy, and pathological examination revealed a tubular adenocarcinoma. Solitary liver and lung metastatic tumors were found 6 and 43 months after the initial presentation, respectively, and sequential metastasectomies were performed. OUTCOMES: The patient survived until 8 years after her initial presentation. The genetic profiles of the resected specimens, primary PDA, and recurrent tumors in the liver and lung possessed identical KRAS mutations at codon 12, whereas there were no mutations in the main tumor suppressor genes, such as TP53, CDKN2A, and SMAD4. Multiplex polymerase chain reaction-based microsatellite instability assay demonstrated microsatellite stability. CONCLUSION: In our case, the patient with pancreatic adenocarcinoma survived for over 8 years following the resection of the primary tumor and resections of metachronous metastatic tumors. The outcome of PDA may be associated with the genetic profile that regulates its biological behavior. Operative management of solitary metastatic tumors may be a therapeutic options for selected patients with pancreatic cancer.


Assuntos
Carcinoma Ductal Pancreático/cirurgia , Neoplasias Pancreáticas/cirurgia , Adulto , Carcinoma Ductal Pancreático/diagnóstico , Carcinoma Ductal Pancreático/genética , Carcinoma Ductal Pancreático/patologia , Feminino , Humanos , Neoplasias Hepáticas/patologia , Neoplasias Hepáticas/secundário , Neoplasias Hepáticas/cirurgia , Neoplasias Pulmonares/patologia , Neoplasias Pulmonares/secundário , Neoplasias Pulmonares/cirurgia , Pancreatectomia , Neoplasias Pancreáticas/diagnóstico , Neoplasias Pancreáticas/genética , Neoplasias Pancreáticas/patologia , Proteínas Proto-Oncogênicas p21(ras)
13.
Nature ; 581(7806): 100-105, 2020 05.
Artigo em Inglês | MEDLINE | ID: mdl-32376951

RESUMO

Immune evasion is a major obstacle for cancer treatment. Common mechanisms of evasion include impaired antigen presentation caused by mutations or loss of heterozygosity of the major histocompatibility complex class I (MHC-I), which has been implicated in resistance to immune checkpoint blockade (ICB) therapy1-3. However, in pancreatic ductal adenocarcinoma (PDAC), which is resistant to most therapies including ICB4, mutations that cause loss of MHC-I are rarely found5 despite the frequent downregulation of MHC-I expression6-8. Here we show that, in PDAC, MHC-I molecules are selectively targeted for lysosomal degradation by an autophagy-dependent mechanism that involves the autophagy cargo receptor NBR1. PDAC cells display reduced expression of MHC-I at the cell surface and instead demonstrate predominant localization within autophagosomes and lysosomes. Notably, inhibition of autophagy restores surface levels of MHC-I and leads to improved antigen presentation, enhanced anti-tumour T cell responses and reduced tumour growth in syngeneic host mice. Accordingly, the anti-tumour effects of autophagy inhibition are reversed by depleting CD8+ T cells or reducing surface expression of MHC-I. Inhibition of autophagy, either genetically or pharmacologically with chloroquine, synergizes with dual ICB therapy (anti-PD1 and anti-CTLA4 antibodies), and leads to an enhanced anti-tumour immune response. Our findings demonstrate a role for enhanced autophagy or lysosome function in immune evasion by selective targeting of MHC-I molecules for degradation, and provide a rationale for the combination of autophagy inhibition and dual ICB therapy as a therapeutic strategy against PDAC.


Assuntos
Adenocarcinoma/imunologia , Autofagia/imunologia , Carcinoma Ductal Pancreático/imunologia , Antígenos de Histocompatibilidade Classe I/imunologia , Antígenos de Histocompatibilidade Classe I/metabolismo , Neoplasias Pancreáticas/imunologia , Evasão Tumoral/imunologia , Adenocarcinoma/tratamento farmacológico , Adenocarcinoma/genética , Adenocarcinoma/patologia , Animais , Apresentação do Antígeno/efeitos dos fármacos , Apresentação do Antígeno/imunologia , Autofagia/efeitos dos fármacos , Autofagia/genética , Linfócitos T CD8-Positivos/efeitos dos fármacos , Linfócitos T CD8-Positivos/imunologia , Carcinoma Ductal Pancreático/tratamento farmacológico , Carcinoma Ductal Pancreático/genética , Carcinoma Ductal Pancreático/patologia , Pontos de Checagem do Ciclo Celular/efeitos dos fármacos , Pontos de Checagem do Ciclo Celular/imunologia , Linhagem Celular Tumoral , Cloroquina/farmacologia , Feminino , Antígenos de Histocompatibilidade Classe I/genética , Humanos , Peptídeos e Proteínas de Sinalização Intracelular/metabolismo , Lisossomos/efeitos dos fármacos , Lisossomos/metabolismo , Masculino , Camundongos , Neoplasias Pancreáticas/tratamento farmacológico , Neoplasias Pancreáticas/genética , Neoplasias Pancreáticas/patologia , Evasão Tumoral/efeitos dos fármacos
14.
Proc Natl Acad Sci U S A ; 117(21): 11471-11482, 2020 05 26.
Artigo em Inglês | MEDLINE | ID: mdl-32385160

RESUMO

Lineage plasticity is a prominent feature of pancreatic ductal adenocarcinoma (PDA) cells, which can occur via deregulation of lineage-specifying transcription factors. Here, we show that the zinc finger protein ZBED2 is aberrantly expressed in PDA and alters tumor cell identity in this disease. Unexpectedly, our epigenomic experiments reveal that ZBED2 is a sequence-specific transcriptional repressor of IFN-stimulated genes, which occurs through antagonism of IFN regulatory factor 1 (IRF1)-mediated transcriptional activation at cooccupied promoter elements. Consequently, ZBED2 attenuates the transcriptional output and growth arrest phenotypes downstream of IFN signaling in multiple PDA cell line models. We also found that ZBED2 is preferentially expressed in the squamous molecular subtype of human PDA, in association with inferior patient survival outcomes. Consistent with this observation, we show that ZBED2 can repress the pancreatic progenitor transcriptional program, enhance motility, and promote invasion in PDA cells. Collectively, our findings suggest that high ZBED2 expression is acquired during PDA progression to suppress the IFN response pathway and to promote lineage plasticity in this disease.


Assuntos
Carcinoma Ductal Pancreático/patologia , Proteínas de Ligação a DNA/metabolismo , Fator Regulador 1 de Interferon/metabolismo , Neoplasias Pancreáticas/patologia , Fatores de Transcrição/metabolismo , Animais , Carcinoma Ductal Pancreático/genética , Carcinoma Ductal Pancreático/metabolismo , Carcinoma Ductal Pancreático/mortalidade , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Imunoprecipitação da Cromatina , Proteínas de Ligação a DNA/genética , Regulação Neoplásica da Expressão Gênica , Humanos , Fator Regulador 1 de Interferon/genética , Interferon gama/farmacologia , Camundongos , Neoplasias Pancreáticas/genética , Neoplasias Pancreáticas/metabolismo , Neoplasias Pancreáticas/mortalidade , Regiões Promotoras Genéticas , Análise de Sobrevida , Fatores de Transcrição/genética
15.
Cell Prolif ; 53(5): e12805, 2020 May.
Artigo em Inglês | MEDLINE | ID: mdl-32364285

RESUMO

OBJECTIVES: Recent observations have emphasized the role of long non-coding RNA (lncRNA) in cancer progression; however, a genetic profile of lncRNAs in pancreatic ductal adenocarcinoma (PDAC) remains an ongoing study. MATERIALS AND METHODS: In this research, RNA sequencing showed that LINC00162 is dramatically increased in patient-derived tumour cell lines (PATC) compared with the human pancreatic nestin-positive epithelial (HPNE) cells. RESULTS: These data were validated in several PDAC cell lines, and significant upregulation of LINC00162 was found in all of them. Knock-down of LINC00162 significantly inhibited the proliferation, colony formation and migration of PATC cells in vitro and suppressed the growth of PATC xenografts in vivo. Overexpression of LINC00162 in PDAC cell lines (AsPc-1) showed consistent results, with significantly increased proliferation, colony formation and migration of AsPc-1 cells, as well as enhanced tumour growth of the AsPc-1 xenografts in vivo. Furthermore, the result of Chromatin immunoprecipitation assay revealed that RelA/p65 directly bound to LINC00162, and the expression of LINC00162 in PDAC decreased after RelA/p65 knock-down, the proliferation ability of AsPc-1 also significantly inhibited after knocking down LINC00162 and RelA/p65 simultaneously, indicating that RelA/p65 directly involve in the transcriptional regulation of LINC00162. CONCLUSIONS: In sum, our results provide first evidence for the role of LINC00162 in promoting PDAC progression and the potential underlying mechanism of LINC00162 overexpression.


Assuntos
Adenocarcinoma/genética , Carcinoma Ductal Pancreático/genética , Neoplasias Pancreáticas/genética , RNA Longo não Codificante/genética , Fator de Transcrição RelA/genética , Adenocarcinoma/patologia , Carcinoma Ductal Pancreático/patologia , Linhagem Celular Tumoral , Movimento Celular/genética , Proliferação de Células/genética , Progressão da Doença , Transição Epitelial-Mesenquimal/genética , Regulação Neoplásica da Expressão Gênica/genética , Humanos , Neoplasias Pancreáticas/patologia , Transcrição Genética/genética , Regulação para Cima/genética
16.
Am J Pathol ; 190(8): 1735-1751, 2020 08.
Artigo em Inglês | MEDLINE | ID: mdl-32339496

RESUMO

Pancreatic ductal adenocarcinoma (PDA) and chronic pancreatitis are characterized by a dense collagen-rich desmoplastic reaction. Discoidin domain receptor 1 (DDR1) is a receptor tyrosine kinase activated by collagens that can regulate cell proliferation, migration, adhesion, and remodeling of the extracellular matrix. To address the role of DDR1 in PDA, Ddr1-null (Ddr-/-) mice were crossed with the KrasG12D/+; Trp53R172H/+; Ptf1aCre/+ (KPC) model of metastatic PDA. Ddr1-/-; KPC mice progress to differentiated PDA but resist progression to poorly differentiated cancer compared with KPC control mice. Strikingly, severe pancreatic atrophy accompanied tumor progression in Ddr1-/-; KPC mice. To further explore the effects of Ddr1 ablation, Ddr1-/- mice were crossed with the KrasG12D/+; Ptf1aCre/+ neoplasia model and subjected to cerulein-induced experimental pancreatitis. Similar to KPC mice, tissue atrophy was a hallmark of both neoplasia and pancreatitis models in the absence of Ddr1. Compared with controls, Ddr1-/- models had increased acinar cell dropout and reduced proliferation with no difference in apoptotic cell death between control and Ddr1-/- animals. In most models, organ atrophy was accompanied by increased fibrillar collagen deposition, suggesting a compensatory response in the absence of this collagen receptor. Overall, these data suggest that DDR1 regulates tissue homeostasis in the neoplastic and injured pancreas.


Assuntos
Células Acinares/patologia , Carcinoma Ductal Pancreático/genética , Receptor com Domínio Discoidina 1/genética , Neoplasias Pancreáticas/genética , Células Acinares/metabolismo , Animais , Carcinoma Ductal Pancreático/metabolismo , Carcinoma Ductal Pancreático/patologia , Linhagem Celular Tumoral , Proliferação de Células/fisiologia , Receptor com Domínio Discoidina 1/metabolismo , Progressão da Doença , Homeostase/fisiologia , Humanos , Camundongos , Camundongos Knockout , Pâncreas/metabolismo , Pâncreas/patologia , Neoplasias Pancreáticas/metabolismo , Neoplasias Pancreáticas/patologia , Transdução de Sinais/fisiologia
17.
Cancer Sci ; 111(6): 2174-2182, 2020 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-32314446

RESUMO

Formalin-fixed paraffin-embedded (FFPE) tissues used for routine pathological diagnosis are valuable for cancer genomic analysis; however, the association between mutation status derived from these specimens and prognosis in pancreatic ductal adenocarcinoma (PDAC) remains unclear. We analyzed 50 cancer-related gene mutations including driver genes in PDAC, using next-generation sequencing (NGS) to clarify the association between gene mutations and prognosis. DNA was extracted from FFPE tissues obtained from 74 patients with untreated resectable PDAC who underwent surgery at our institution between 2013 and 2018. Fifty of the 74 patients with DNA extracts from FFPE samples suitable for NGS were analyzed. The prevalence of driver gene mutations was as follows: 84% for KRAS, 62% for TP53, 32% for SMAD4, and 18% for CDKN2A. There were no cases of single SMAD4 mutations; its rate of coincidence with KRAS or TP53 mutations was 30% and 2%, respectively. The combination of KRAS and SMAD4 mutations resulted in significantly shorter relapse-free survival (RFS; median survival time [MST], 12.3 vs. 28.9 months, P = .014) and overall survival (OS; MST, 22.3 months vs. not reached, P = .048). On multivariate analysis, the combination of KRAS and SMAD4 mutations was an independent prognostic factor for RFS (hazard ratio [HR] 4.218; 95% confidence interval [CI], 1.77-10.08; P = .001) and OS (HR 6.730; 95% CI, 1.93-23.43; P = .003). The combination of KRAS and SMAD4 mutations in DNA obtained from FFPE tissues is an independent poor prognostic factor in PDAC.


Assuntos
Biomarcadores Tumorais/genética , Carcinoma Ductal Pancreático/genética , Neoplasias Pancreáticas/genética , Proteínas Proto-Oncogênicas p21(ras)/genética , Proteína Smad4/genética , Adulto , Idoso , Idoso de 80 Anos ou mais , Carcinoma Ductal Pancreático/mortalidade , Análise Mutacional de DNA/métodos , Feminino , Formaldeído , Sequenciamento de Nucleotídeos em Larga Escala/métodos , Humanos , Masculino , Pessoa de Meia-Idade , Mutação , Neoplasias Pancreáticas/mortalidade , Inclusão em Parafina , Prognóstico , Fixação de Tecidos
18.
PLoS One ; 15(4): e0231835, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32310997

RESUMO

Pancreatic ductal adenocarcinoma (PDAC) is among the most lethal cancers. Known risk factors for this disease are currently insufficient in predicting mortality. In order to better prognosticate patients with PDAC, we identified 20 genes by utilizing publically available high-throughput transcriptomic data from GEO, TCGA and ICGC which are associated with overall survival and event-free survival. A score generated based on the expression matrix of these genes was validated in two independent cohorts. We find that this "Pancreatic cancer prognostic score 20 -PPS20" is independent of the confounding factors in multivariate analyses, is dramatically elevated in metastatic tissue compared to primary tumor, and is higher in primary tumors compared to normal pancreatic tissue. Transcriptomic analyses show that tumors with low PPS20 have overall more immune cell infiltration and a higher CD8 T cell/Treg ratio when compared to those with high PPS20. Analyses of proteomic data from TCGA PAAD indicated higher levels of Cyclin B1, RAD51, EGFR and a lower E-cadherin/Fibronectin ratio in tumors with high PPS20. The PPS20 score defines not only prognostic and biological sub-groups but can predict response to targeted therapy as well. Overall, PPS20 is a stronger and more robust transcriptomic signature when compared to similar, previously published gene lists.


Assuntos
Carcinoma Ductal Pancreático/genética , Perfilação da Expressão Gênica , Regulação Neoplásica da Expressão Gênica , Neoplasias Pancreáticas/genética , Carcinoma Ductal Pancreático/diagnóstico , Carcinoma Ductal Pancreático/tratamento farmacológico , Humanos , Terapia de Alvo Molecular , Neoplasias Pancreáticas/diagnóstico , Neoplasias Pancreáticas/tratamento farmacológico , Prognóstico , Análise de Sobrevida
19.
Nat Cell Biol ; 22(4): 425-438, 2020 04.
Artigo em Inglês | MEDLINE | ID: mdl-32203416

RESUMO

Piwi proteins are normally restricted in germ cells to suppress transposons through associations with Piwi-interacting RNAs (piRNAs), but they are also frequently activated in many types of human cancers. A great puzzle is the lack of significant induction of corresponding piRNAs in cancer cells, as we document here in human pancreatic ductal adenocarcinomas (PDACs), which implies that such germline-specific proteins are somehow hijacked to promote tumorigenesis through a different mode of action. Here, we show that in the absence of piRNAs, human PIWIL1 in PDAC functions as an oncoprotein by activating the anaphase promoting complex/cyclosome (APC/C) E3 complex, which then targets a critical cell adhesion-related protein, Pinin, to enhance PDAC metastasis. This is in contrast to piRNA-dependent PIWIL1 ubiquitination and removal by APC/C during late spermiogenesis. These findings unveil a piRNA-dependent mechanism to switch PIWIL1 from a substrate in spermatids to a co-activator of APC/C in human cancer cells.


Assuntos
Adenocarcinoma/genética , Proteínas Argonauta/genética , Carcinoma Ductal Pancreático/genética , Moléculas de Adesão Celular/genética , Regulação Neoplásica da Expressão Gênica , Proteínas Nucleares/genética , Neoplasias Pancreáticas/genética , RNA Interferente Pequeno/genética , Adenocarcinoma/metabolismo , Adenocarcinoma/patologia , Anáfase , Ciclossomo-Complexo Promotor de Anáfase/genética , Ciclossomo-Complexo Promotor de Anáfase/metabolismo , Animais , Proteínas Argonauta/metabolismo , Carcinogênese/genética , Carcinogênese/metabolismo , Carcinoma Ductal Pancreático/metabolismo , Carcinoma Ductal Pancreático/patologia , Moléculas de Adesão Celular/metabolismo , Linhagem Celular Tumoral , Proliferação de Células , Humanos , Metástase Linfática , Masculino , Camundongos , Camundongos Knockout , Camundongos Nus , Proteínas Nucleares/metabolismo , Neoplasias Pancreáticas/metabolismo , Neoplasias Pancreáticas/patologia , RNA Interferente Pequeno/metabolismo , Transdução de Sinais , Espermatogênese/genética , Ubiquitinação , Ensaios Antitumorais Modelo de Xenoenxerto
20.
J Cancer Res Clin Oncol ; 146(4): 897-907, 2020 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-32146565

RESUMO

INTRODUCTION: Pancreatic ductal adenocarcinoma (PDAC) is a very aggressive cancer. There are various sub-cellular events (both genetic and epigenetic) that get dysregulated leading to tumorigenesis. Methylation in promoters of tumor suppressor genes is one of these epigenetic phenomena contributing to the pathogenesis of cancer. Genes analyzed for promoter methylation status in this study namely SPARC (Secreted Protein Acidic and Rich in Cysteine, UCHL1 (ubiquitin carboxy-terminal hydrolase L1), NPTX2 (neuronal pentraxin 2), PENK (proenkephalin) had been studied in pancreatic cancer, but there is a need to check methylation in these genes as circulatory non-invasive markers. This study analyzed the absolute quantification of methylation levels of SPARC, UCHL1, PENK, and NPTX2 genes promoters in PDAC patients as well as in chronic pancreatitis (CP) patients and healthy subjects (HC) and evaluated its clinical significance in PDAC. MATERIALS AND METHODS: The study included 65 PDAC patients, 25 CP patients, and 25 healthy controls. DNA was extracted from their plasma samples and subsequently given bisulfite treatment. Absolute quantization of methylated and unmethylated copies of gene promoters of all the four genes was performed using real-time PCR (SYBR green) by the standard curve method. Methylation levels were expressed as methylation index (MI) for each gene in each patient. MI was calculated from absolute copy numbers as follows: MI-methylated copy number/methylated copy number + unmethylated copy number). These indices were used to compare gene methylation levels within different groups and to correlate with clinicopathological features and survival of pancreatic cancer patients. An appropriate statistical analysis was applied. RESULTS: Methylation indices for all the four genes in PDAC cases were found to be significantly higher as compared to that in healthy individuals. SPARC MI values were found to differentiate early-stage PDAC patients from CP patients. PDAC patients with the metastasized disease and stage IV disease were found to have high MI for the SPARC gene as well as for the NPTX2 gene, while a higher UCHL1 methylation index was found to correlate with an advanced stage of the disease. Higher MI values for SPARC and NPTX2 genes were found to associate with poor survival in patients with PDAC. CONCLUSION: Methylation load in the form of MI for each of the four genes assessed in plasma may emerge as a non-invasive biomarker to differentiate pancreatic cancer from healthy individuals. But only SPARC and NPTX2 hypermethylation were able to distinguish pancreatic cancer from chronic pancreatitis. Association of aberrant methylation in SPARC and NPTX2 gene with metastasis and poor survival of patients suggest the role of methylation in these genes as prognostic markers.


Assuntos
Carcinoma Ductal Pancreático/genética , DNA Tumoral Circulante/genética , Metilação de DNA , Genes Supressores de Tumor , Neoplasias Pancreáticas/genética , Proteína C-Reativa/genética , Carcinoma Ductal Pancreático/sangue , Estudos de Casos e Controles , Diferenciação Celular/genética , DNA Tumoral Circulante/sangue , Encefalinas/genética , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Proteínas do Tecido Nervoso/genética , Osteonectina/genética , Neoplasias Pancreáticas/sangue , Pancreatite Crônica/sangue , Pancreatite Crônica/genética , Regiões Promotoras Genéticas , Precursores de Proteínas/genética , Ubiquitina Tiolesterase/genética
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