PTEN Is a Major Tumor Suppressor in Pancreatic Ductal Adenocarcinoma and Regulates an NF-κB–Cytokine Network

Ying, Haoqiang; Elpek, Kutlu G.; Vinjamoori, Anant; Zimmerman, Stephanie M.; Chu, Gerald C.; Yan, Haiyan; Fletcher-Sananikone, Eliot; Zhang, Hailei; Liu, Yingchun; Wang, Wei; Ren, Xiaojia; Zheng, Hongwu; Kimmelman, Alec C.; Paik, Ji Hye; Lim, Carol S.; Perry, Samuel R.; Jiang, Shan; Malinn, Brian; Protopopov, Alexei; Colla, Simona; Xiao, Yonghong; Hezel, Aram F.; Bardeesy, Nabeel; Turley, Shannon J.; Wang, Y. Alan; Chin, Lynda; Thayer, Sarah P.; DePinho, Ronald A.

doi:10.1158/2159-8290.cd-11-0031

Cited by 195 publications

(188 citation statements)

References 46 publications

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“…Involvement of PI3K activity in pancreatic cancerogenesis had previously been suggested by the protumorigenic effect of pancreatic-restricted loss of the PTEN enzyme, which reverses PI3K activity (Stanger et al 2005;Hill et al 2010;Ying et al 2011;Mann et al 2012). In tissue other than the pancreas, Pten deletion-induced tumorigenesis was shown to be PI3K isoform-specific.…”

Section: Discussionmentioning

confidence: 93%

Pancreatic cell plasticity and cancer initiation induced by oncogenic Kras is completely dependent on wild-type PI 3-kinase p110α

Baer¹,

Cintas²,

et al. 2014

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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 p110a 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, p110b, did not prevent preneoplastic lesion initiation. p110a signaling through small GTPase Rho and actin cytoskeleton controls the reprogramming of acinar cells and regulates cell morphology in vivo and in vitro. Finally, p110a 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 p110a cellular output differs depending on the epithelial transformation stage and demonstrate that the PI3K p110a 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.

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Section: Discussionmentioning

confidence: 93%

Pancreatic cell plasticity and cancer initiation induced by oncogenic Kras is completely dependent on wild-type PI 3-kinase p110α

Baer¹,

Cintas²,

et al. 2014

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“…This observation, coupled with the multiple cells of origin for PanIN lesions (Gidekel Friedlander et al 2009;Kopp et al 2012) and the established critical role of epigenetic modifications during cellular development and lineage specification (Orkin and Hochedlinger 2011), prompts speculation that these chromatin modulators may lie at the nexus of cellular plasticity processes that provide a permissive developmental state for oncogenic KRAS-driven transformation across various cell types. Beyond cellular differentiation, SWI/ SNF and MLL may also impact other hallmarks of cancer such as cell cycle and apoptosis control via epigenetic regulation of the INK4A or PTEN loci, which are silenced in a significant fraction of human PDAC cases (Kia et al 2008;Watanabe et al 2011;Ying et al 2011;Singh and Ellenrieder 2013). Therefore, the mutation or deletion of chromatin modulators may also participate in the epigenetic inactivation of key tumor suppressors to promote neoplastic proliferation.…”

Section: Pdac Epigeneticsmentioning

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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“…Following seeding, cells were exposed to ASA (2.5-5.0 mM) or vehicle for 7 days and colonies were stained with 0.2% crystal violet in 80% methanol. 23 After taking photographs, the colonies were counted and then they were dissolved in 10% acetic acid and OD was measured at 600 nm using a VMax Microplate Reader with the current version of SoftMax Pro (Molecular Devices).…”

Section: Immunostaining For Proliferative Indexmentioning

confidence: 99%

Aspirin blocks growth of breast tumor cells and tumor-initiating cells and induces reprogramming factors of mesenchymal to epithelial transition

Maity

Das

et al. 2015

Laboratory Investigation

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Acetylsalicylic acid (ASA), also known as aspirin, a classic, nonsteroidal, anti-inflammatory drug (NSAID), is widely used to relieve minor aches and pains and to reduce fever. Epidemiological studies and other experimental studies suggest that ASA use reduces the risk of different cancers including breast cancer (BC) and may be used as a chemopreventive agent against BC and other cancers. These studies have raised the tempting possibility that ASA could serve as a preventive medicine for BC. However, lack of in-depth knowledge of the mechanism of action of ASA reshapes the debate of risk and benefit of using ASA in prevention of BC. Our studies, using in vitro and in vivo tumor xenograft models, show a strong beneficial effect of ASA in the prevention of breast carcinogenesis. We find that ASA not only prevents breast tumor cell growth in vitro and tumor growth in nude mice xenograft model through the induction of apoptosis, but also significantly reduces the self-renewal capacity and growth of breast tumor-initiating cells (BTICs)/breast cancer stem cells (BCSCs) and delays the formation of a palpable tumor. Moreover, ASA regulates other pathophysiological events in breast carcinogenesis, such as reprogramming the mesenchymal to epithelial transition (MET) and delaying in vitro migration in BC cells. The tumor growth-inhibitory and reprogramming roles of ASA could be mediated through inhibition of TGF-β/ SMAD4 signaling pathway that is associated with growth, motility, invasion, and metastasis in advanced BCs. Collectively, ASA has a therapeutic or preventive potential by attacking possible target such as TGF-β in breast carcinogenesis.

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PTEN Is a Major Tumor Suppressor in Pancreatic Ductal Adenocarcinoma and Regulates an NF-κB–Cytokine Network

Cited by 195 publications

References 46 publications

Pancreatic cell plasticity and cancer initiation induced by oncogenic Kras is completely dependent on wild-type PI 3-kinase p110α

Pancreatic cell plasticity and cancer initiation induced by oncogenic Kras is completely dependent on wild-type PI 3-kinase p110α

Genetics and biology of pancreatic ductal adenocarcinoma

Aspirin blocks growth of breast tumor cells and tumor-initiating cells and induces reprogramming factors of mesenchymal to epithelial transition

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