GNASR201H and KrasG12D cooperate to promote murine pancreatic tumorigenesis recapitulating human intraductal papillary mucinous neoplasm

Taki, Katsunobu; Ohmuraya, Masaki; Tanji, Etsuko; Komatsu, Hirotake; Hashimoto, Daisuke; Semba, Kei; Araki, Kimi; Kawaguchi, Yoshiya; Baba, Hideo; Furukawa, Toru

doi:10.1038/onc.2015.294

Cited by 79 publications

(71 citation statements)

References 21 publications

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“…The notion of distinct lesions driving the development of IPMN and MCN is reinforced by recent sequencing studies that have identified IPMN/ MCN-specific mutations in GNAS and RNF43 (Wu et al 2011a,b;Dal Molin et al 2013). While one recent study in an inducible GEMM has shown that Gnas mutation cooperates with oncogenic Kras to promote the formation of IPMN (Taki et al 2015), how these signature mutations function to drive the cystic phenotype during exocrine neoplasia remains an understudied area.…”

Section: Pancreatic Ductal Adenocarcinoma (Pdac) Pathogenesismentioning

confidence: 98%

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: Pancreatic Ductal Adenocarcinoma (Pdac) Pathogenesismentioning

confidence: 98%

Genetics and biology of pancreatic ductal adenocarcinoma

et al. 2016

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“…IPMN formation has been observed in several transgenic mouse models, including those with concomitant activation of TGF-alpha, stimulation of Gs-alpha subunit GNAS, deletion of Brg1 , or attenuated Smad4 expression in the context of oncogenic Kras (Bardeesy et al, 2006; Siveke et al, 2007; Taki et al, 2015; von Figura et al, 2014a). Of particular interest is the observation that despite distinct morphological and gene expression signatures of IPMN and PanIN lesions, the resulting tumors are both classified as PDA.…”

Section: Intraductal Papillary Mucinous Neoplasm (Ipmn) Derived Pdamentioning

confidence: 99%

Regulation of Cellular Identity in Cancer

Roy

Hebrok

2015

Developmental Cell

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Summary 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.

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“…In general, GNAS mutations are often in more advanced lesions. A recent experimental study demonstrated that activating mutations in GNAS and KRAS cooperatively promote pancreatic tumorigenesis, which recapitulates IPMN (37).…”

Section: Current Practice and The Updates On The Genomic Fieldmentioning

confidence: 99%