What We Have Learned About Pancreatic Cancer From Mouse Models

Pérez–Mancera, Pedro A.; Guerra, Carmen; Barbacid, Mariano; Tuveson, David A.

doi:10.1053/j.gastro.2012.03.002

Cited by 154 publications

(135 citation statements)

References 131 publications

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“…This mutation is a key initiator, as evidenced by its presence in PanIN lesions (Kanda et al 2012;Murphy et al 2013) and the production of PanIN lesions in oncogenic Kras-driven GEMMs (Hezel et al 2006;Perez-Mancera et al 2012a). While some PDAC cell lines in two-dimensional (2D) culture can tolerate shRNA-mediated KRAS extinction (Singh et al 2009), most PDAC cells remain highly addicted to oncogenic KRAS for tumor maintenance in three-dimensional (3D) culture (Zhang et al 2006;Fujita-Sato et al 2015) and inducible oncogenic Kras GEMMs with advanced tumors (Collins et al 2012;Ying et al 2012).…”

Section: The Kras Oncogene Signaling Networkmentioning

confidence: 99%

Genetics and biology of pancreatic ductal adenocarcinoma

et al. 2016

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With 5-year survival rates remaining constant at 6% and rising incidences associated with an epidemic in obesity and metabolic syndrome, pancreatic ductal adenocarcinoma (PDAC) is on track to become the second most common cause of cancer-related deaths by 2030. The high mortality rate of PDAC stems primarily from the lack of early diagnosis and ineffective treatment for advanced tumors. During the past decade, the comprehensive atlas of genomic alterations, the prominence of specific pathways, the preclinical validation of such emerging targets, sophisticated preclinical model systems, and the molecular classification of PDAC into specific disease subtypes have all converged to illuminate drug discovery programs with clearer clinical path hypotheses. A deeper understanding of cancer cell biology, particularly altered cancer cell metabolism and impaired DNA repair processes, is providing novel therapeutic strategies that show strong preclinical activity. Elucidation of tumor biology principles, most notably a deeper understanding of the complexity of immune regulation in the tumor microenvironment, has provided an exciting framework to reawaken the immune system to attack PDAC cancer cells. While the long road of translation lies ahead, the path to meaningful clinical progress has never been clearer to improve PDAC patient survival. Pancreatic ductal adenocarcinoma (PDAC) pathogenesisOn gross inspection, PDAC presents as a poorly demarcated, firm white-yellow mass, with the surrounding nonmalignant pancreas typically showing atrophy, fibrosis, and dilated ducts due to the obstructive effects of expanding carcinoma. Microscopically, these neoplasms vary from well-differentiated gland-forming carcinomas to poorly differentiated "sarcomatoid" carcinomas diagnosed only upon immunolabeling due to predominant mesenchymal features (Hruban et al. 2007). PDAC evolves from well-defined precursor lesions that, in the context of their genetic features, define the genetic progression model of pancreatic carcinogenesis (Yachida et al. 2010). Early disease histology manifests as several distinct types of precursor lesions-the most common are microscopic pancreatic intraepithelial neoplasia (PanIN), followed by the macroscopic cysts; namely, the intraductal papillary mucinous neoplasm (IPMN) and mucinous cystic neoplasm (MCN) (Matthaei et al. 2011). Since most PDAC cases become clinically apparent at advanced stages, major opportunities to reduce mortality rest with diagnostics and treatments that would enable the reliable identification and elimination of high-risk precursor lesions. Thus, the identification of these precursor lesions has provided an essential framework to define the genomic features that drive progression to advanced disease and develop effective screening and targeted therapeutics for earlier stage disease (Eser et al. 2011).The noninvasive PanIN lesions were formerly classified into three grades according to the extent of cytological and architectural atypia: PanIN1A (flat lesion) and PanIN1B (micropapillary...

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Section: The Kras Oncogene Signaling Networkmentioning

confidence: 99%

Genetics and biology of pancreatic ductal adenocarcinoma

et al. 2016

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“…New insights in PDAC initiation show that adult exocrine acinar cells under stress can dedifferentiate and gain metaplastic ductal characteristics (referred to as acinar-to-ductal metaplasia, ADM). There is compelling evidence from mouse models that ADM is a precursor lesion of PDAC (2,3). ADM also occurs in pancreatitis, which may explain why pancreatitis is a major risk factor for PDAC (2,3).…”

Section: Introductionmentioning

confidence: 99%

“…There is compelling evidence from mouse models that ADM is a precursor lesion of PDAC (2,3). ADM also occurs in pancreatitis, which may explain why pancreatitis is a major risk factor for PDAC (2,3). Prevention of ADM and maintenance of acinar cell differentiation could suppress pancreatic carcinogenesis.…”

Section: Introductionmentioning

confidence: 99%

Sirtuin-1 Regulates Acinar-to-Ductal Metaplasia and Supports Cancer Cell Viability in Pancreatic Cancer

et al. 2013

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The exocrine pancreas can undergo acinar-to-ductal metaplasia (ADM), as in the case of pancreatitis where precursor lesions of pancreatic ductal adenocarcinoma (PDAC) can arise. The NAD þ -dependent protein deacetylase Sirtuin-1 (Sirt1) has been implicated in carcinogenesis with dual roles depending on its subcellular localization. In this study, we examined the expression and the role of Sirt1 in different stages of pancreatic carcinogenesis, i.e. ADM models and established PDAC. In addition, we analyzed the expression of KIAA1967, a key mediator of Sirt1 function, along with potential Sirt1 downstream targets. Sirt1 was co-expressed with KIAA1967 in the nuclei of normal pancreatic acinar cells. In ADM, Sirt1 underwent a transient nuclear-tocytoplasmic shuttling. Experiments where during ADM, we enforced repression of Sirt1 shuttling, inhibition of Sirt1 activity or modulation of its expression, all underscore that the temporary decrease of nuclear and increase of cytoplasmic Sirt1 stimulate ADM. Our results further underscore that important transcriptional regulators of acinar differentiation, that is, Pancreatic transcription factor-1a and b-catenin can be deacetylated by Sirt1. Inhibition of Sirt1 is effective in suppression of ADM and in reducing cell viability in established PDAC tumors. KIAA1967 expression is differentially downregulated in PDAC and impacts on the sensitivity of PDAC cells to the Sirt1/2 inhibitor Tenovin-6. In PDAC, acetylation of b-catenin is not affected, unlike p53, a well-characterized Sirt1-regulated protein in tumor cells. Our results reveal that Sirt1 is an important regulator and potential therapeutic target in pancreatic carcinogenesis. Cancer Res; 73(7); 2357-67. Ó2012 AACR.

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“…Although these findings provide evidence of pathological plasticity associated with the early stages of malignant transformation, it is unclear whether Kras-dependent reprogramming is unique to pancreatic tumors or whether it takes place in a broad range of neoplasms. Moreover, the concept of plasticity itself has been challenged, as it remains unclear why only some, but not all, cells in the adult lung, pancreas, and colon have the capacity to give rise to Kras-driven tumors (10,12,18,19). In this study, we sought to address this question and to determine the role of cellular plasticity in the origin of Kras-mediated transformation.…”

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confidence: 99%

Direct reprogramming by oncogenic Ras and Myc

Ischenko

Zhi

Moll

et al. 2013

Proc. Natl. Acad. Sci. U.S.A.

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Genetically or epigenetically defined reprogramming is a hallmark of cancer cells. However, a causal association between genome reprogramming and cancer has not yet been conclusively established. In particular, little is known about the mechanisms that underlie metastasis of cancer, and even less is known about the identity of metastasizing cancer cells. In this study, we used a model of conditional expression of oncogenic KrasG12D allele in primary mouse cells to show that reprogramming and dedifferentiation is a fundamental early step in malignant transformation and cancer initiation. Our data indicate that stable expression of activated KrasG12D confers on cells a large degree of phenotypic plasticity that predisposes them to neoplastic transformation and acquisition of stem cell characteristics. We have developed a genetically tractable model system to investigate the origins and evolution of metastatic pancreatic cancer cells. We show that metastatic conversion of KrasG12D-expressing cells that exhibit different degrees of differentiation and malignancy can be reconstructed in cell culture, and that the proto-oncogene c-Myc controls the generation of self-renewing metastatic cancer cells. Collectively, our results support a model wherein non-stem cancer cells have the potential to dedifferentiate and acquire stem cell properties as a direct consequence of oncogene-induced plasticity. Moreover, the disturbance in the normally existing dynamic equilibrium between cancer stem cells and non-stem cancer cells allows the formation of cancer stem cells with high metastatic capacity at any time during cancer progression.

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What We Have Learned About Pancreatic Cancer From Mouse Models

Cited by 154 publications

References 131 publications

Genetics and biology of pancreatic ductal adenocarcinoma

Genetics and biology of pancreatic ductal adenocarcinoma

Sirtuin-1 Regulates Acinar-to-Ductal Metaplasia and Supports Cancer Cell Viability in Pancreatic Cancer

Direct reprogramming by oncogenic Ras and Myc

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