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1.
Genes Dev ; 28(23): 2621-35, 2014 Dec 01.
Artigo em Inglês | MEDLINE | ID: mdl-25452273

RESUMO

Increased PI 3-kinase (PI3K) signaling in pancreatic ductal adenocarcinoma (PDAC) correlates with poor prognosis, but the role of class I PI3K isoforms during its induction remains unclear. Using genetically engineered mice and pharmacological isoform-selective inhibitors, we found that the p110α PI3K isoform is a major signaling enzyme for PDAC development induced by a combination of genetic and nongenetic factors. Inactivation of this single isoform blocked the irreversible transition of exocrine acinar cells into pancreatic preneoplastic ductal lesions by oncogenic Kras and/or pancreatic injury. Hitting the other ubiquitous isoform, p110ß, did not prevent preneoplastic lesion initiation. p110α signaling through small GTPase Rho and actin cytoskeleton controls the reprogramming of acinar cells and regulates cell morphology in vivo and in vitro. Finally, p110α was necessary for pancreatic ductal cancers to arise from Kras-induced preneoplastic lesions by increasing epithelial cell proliferation in the context of mutated p53. Here we identify an in vivo context in which p110α cellular output differs depending on the epithelial transformation stage and demonstrate that the PI3K p110α is required for PDAC induced by oncogenic Kras, the key driver mutation of PDAC. These data are critical for a better understanding of the development of this lethal disease that is currently without efficient treatment.


Assuntos
Carcinoma Ductal Pancreático/genética , Carcinoma Ductal Pancreático/fisiopatologia , Classe Ia de Fosfatidilinositol 3-Quinase/genética , Classe Ia de Fosfatidilinositol 3-Quinase/metabolismo , Neoplasias Pancreáticas/genética , Neoplasias Pancreáticas/fisiopatologia , Proteínas Proto-Oncogênicas p21(ras)/metabolismo , Animais , Animais Geneticamente Modificados , Proliferação de Células , Células Epiteliais/citologia , Inativação Gênica , Humanos , Camundongos , Mutação , Proteínas Proto-Oncogênicas p21(ras)/genética , Transdução de Sinais
2.
Br J Cancer ; 113(11): 1590-8, 2015 Dec 01.
Artigo em Inglês | MEDLINE | ID: mdl-26512875

RESUMO

BACKGROUND: Pancreatic ductal adenocarcinoma (PDAC) is one of the most lethal malignancies with a mortality that is almost identical to incidence. Because early detected PDAC is potentially curable, blood-based biomarkers that could detect currently developing neoplasia would improve patient survival and management. PDAC develops from pancreatic intraepithelial neoplasia (PanIN) lesions, graded from low grade (PanIN1) to high grade (PanIN3). We made the hypothesis that specific proteomic signatures from each precancerous stage exist and are detectable in plasma. METHODS: We explored the peptide profiles of microdissected PanIN cells and of plasma samples corresponding to the different PanIN grade from genetically engineered mouse models of PDAC using capillary electrophoresis coupled to mass spectrometry (CE-MS) and Chip-MS/MS. RESULTS: We successfully characterised differential peptides profiles from PanIN microdissected cells. We found that plasma from tumor-bearing mice and age-matched controls exhibit discriminative peptide signatures. We also determined plasma peptide signatures corresponding to low- and high-grade precancerous step present in the mice pancreas using the two mass spectrometry technologies. Importantly, we identified biomarkers specific of PanIN3. CONCLUSIONS: We demonstrate that benign and advanced PanIN lesions display distinct plasma peptide patterns. This strongly supports the perspectives of developing a non-invasive screening test for prediction and early detection of PDAC.


Assuntos
Biomarcadores Tumorais/sangue , Carcinoma in Situ/sangue , Carcinoma Ductal Pancreático/sangue , Proteínas de Neoplasias/sangue , Neoplasias Pancreáticas/sangue , Peptídeos/sangue , Lesões Pré-Cancerosas/sangue , Animais , Biomarcadores Tumorais/análise , Carcinoma in Situ/química , Carcinoma in Situ/patologia , Carcinoma Ductal Pancreático/química , Modelos Animais de Doenças , Camundongos , Proteínas de Neoplasias/análise , Neoplasias Pancreáticas/química , Peptídeos/análise , Lesões Pré-Cancerosas/química , Lesões Pré-Cancerosas/patologia , Análise Serial de Proteínas , Proteoma/análise
3.
EMBO Mol Med ; 13(7): e13502, 2021 07 07.
Artigo em Inglês | MEDLINE | ID: mdl-34033220

RESUMO

Pancreatic ductal adenocarcinoma (PDAC) patients frequently suffer from undetected micro-metastatic disease. This clinical situation would greatly benefit from additional investigation. Therefore, we set out to identify key signalling events that drive metastatic evolution from the pancreas. We searched for a gene signature that discriminate localised PDAC from confirmed metastatic PDAC and devised a preclinical protocol using circulating cell-free DNA (cfDNA) as an early biomarker of micro-metastatic disease to validate the identification of key signalling events. An unbiased approach identified, amongst actionable markers of disease progression, the PI3K pathway and a distinctive PI3Kα activation signature as predictive of PDAC aggressiveness and prognosis. Pharmacological or tumour-restricted genetic PI3Kα-selective inhibition prevented macro-metastatic evolution by hindering tumoural cell migratory behaviour independently of genetic alterations. We found that PI3Kα inhibition altered the quantity and the species composition of the produced lipid second messenger PIP3 , with a selective decrease of C36:2 PI-3,4,5-P3 . Tumoural PI3Kα inactivation prevented the accumulation of pro-tumoural CD206-positive macrophages in the tumour-adjacent tissue. Tumour cell-intrinsic PI3Kα promotes pro-metastatic features that could be pharmacologically targeted to delay macro-metastatic evolution.


Assuntos
Adenocarcinoma , Carcinoma Ductal Pancreático , Neoplasias Pancreáticas , Carcinoma Ductal Pancreático/genética , Humanos , Macrófagos , Neoplasias Pancreáticas/genética , Fosfatidilinositol 3-Quinases/genética
4.
JCI Insight ; 4(21)2019 11 01.
Artigo em Inglês | MEDLINE | ID: mdl-31672935

RESUMO

Pancreatic ductal adenocarcinoma (PDAC) relies on hyperactivated protein synthesis. Consistently, human and mouse PDAC lose expression of the translational repressor and mTOR target 4E-BP1. Using genome-wide polysome profiling, we here explore mRNAs whose translational efficiencies depend on the mTOR/4E-BP1 axis in pancreatic cancer cells. We identified a functional enrichment for mRNAs encoding DNA replication and repair proteins, including RRM2 and CDC6. Consequently, 4E-BP1 depletion favors DNA repair and renders DNA replication insensitive to mTOR inhibitors, in correlation with a sustained protein expression of CDC6 and RRM2, which is inversely correlated with 4E-BP1 expression in PDAC patient samples. DNA damage and pancreatic lesions induced by an experimental pancreatitis model uncover that 4E-BP1/2-deleted mice display an increased acinar cell proliferation and a better recovery than WT animals. Targeting translation, independently of 4E-BP1 status, using eIF4A RNA helicase inhibitors (silvestrol derivatives) selectively modulates translation and limits CDC6 expression and DNA replication, leading to reduced PDAC tumor growth. In summary, 4E-BP1 expression loss during PDAC development induces selective changes in translation of mRNA encoding DNA replication and repair protein. Importantly, targeting protein synthesis by eIF4A inhibitors circumvents PDAC resistance to mTOR inhibition.


Assuntos
Proteínas Adaptadoras de Transdução de Sinal/genética , Carcinoma Ductal Pancreático/metabolismo , Proteínas de Ciclo Celular/genética , Replicação do DNA , Fator de Iniciação 4A em Eucariotos/antagonistas & inibidores , Neoplasias Pancreáticas/metabolismo , Animais , Carcinoma Ductal Pancreático/genética , Carcinoma Ductal Pancreático/patologia , Linhagem Celular Tumoral , Humanos , Camundongos , Neoplasias Pancreáticas/genética , Neoplasias Pancreáticas/patologia , Biossíntese de Proteínas , Serina-Treonina Quinases TOR/antagonistas & inibidores
5.
Adv Biol Regul ; 59: 19-35, 2015 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-26166735

RESUMO

Pancreatic cancer belongs to the incurable family of solid cancers. Despite of a recent better understanding its molecular biology, and an increased number of clinical trials, there is still a lack for innovative targeted therapies to fight this deadly malignancy. PI3K/Akt signalling is one of the most commonly deregulated signalling pathways in cancer, which explains the massive attention from many pharmaceutical companies over the ten past years on these signalling molecules. The already developed small molecule inhibitors are currently under clinical trial in various cancer types. Class I PI3Ks have 4 isoforms for which the role in physiology starts to be well described in the literature. Data are more unclear for their differential involvement in oncogenesis. In this review, we will discuss about the cognitive and therapeutic potential of targeting this signalling pathway and in particular Class I PI3K isoforms for pancreatic cancer treatment. Isoform-specificity of PI3K inhibitors are currently designed to achieve the same goal as pan-PI3K inhibitors but without potential adverse effects. We will discuss if such strategy is relevant in pancreatic adenocarcinoma.


Assuntos
Neoplasias Pancreáticas/enzimologia , Neoplasias Pancreáticas/metabolismo , Fosfatidilinositol 3-Quinases/metabolismo , Isoformas de Proteínas/metabolismo , Proteínas Proto-Oncogênicas c-akt/metabolismo , Animais , Humanos , Fosfatidilinositol 3-Quinases/genética , Isoformas de Proteínas/genética , Proteínas Proto-Oncogênicas c-akt/genética , Transdução de Sinais
6.
Oncotarget ; 6(34): 35880-92, 2015 Nov 03.
Artigo em Inglês | MEDLINE | ID: mdl-26416424

RESUMO

p27Kip1 (p27) is a negative regulator of proliferation and a tumor suppressor via the inhibition of cyclin-CDK activity in the nucleus. p27 is also involved in the regulation of other cellular processes, including transcription by acting as a transcriptional co-repressor. Loss of p27 expression is frequently observed in pancreatic adenocarcinomas in human and is associated with decreased patient survival. Similarly, in a mouse model of K-Ras-driven pancreatic cancer, loss of p27 accelerates tumor development and shortens survival, suggesting an important role for p27 in pancreatic tumorigenesis. Here, we sought to determine how p27 might contribute to early events leading to tumor development in the pancreas. We found that K-Ras activation in the pancreas causes p27 mislocalization at pre-neoplastic stages. Moreover, loss of p27 or expression of a mutant p27 that does not bind cyclin-CDKs causes the mislocalization of several acinar polarity markers associated with metaplasia and induces the nuclear expression of Sox9 and Pdx1 two transcription factors involved in acinar-to-ductal metaplasia. Finally, we found that p27 directly represses transcription of Sox9, but not that of Pdx1. Thus, our results suggest that K-Ras activation, the earliest known event in pancreatic carcinogenesis, may cause loss of nuclear p27 expression which results in derepression of Sox9, triggering reprogramming of acinar cells and metaplasia.


Assuntos
Inibidor de Quinase Dependente de Ciclina p27/deficiência , Pâncreas/metabolismo , Pâncreas/patologia , Fatores de Transcrição SOX9/biossíntese , Animais , Linhagem Celular Tumoral , Transformação Celular Neoplásica/metabolismo , Inibidor de Quinase Dependente de Ciclina p27/genética , Inibidor de Quinase Dependente de Ciclina p27/metabolismo , Células HEK293 , Células HeLa , Humanos , Metaplasia , Camundongos , Camundongos Knockout , Fatores de Transcrição SOX9/genética , Fatores de Transcrição SOX9/metabolismo , Transdução de Sinais
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