Mutant Kras co-opts a proto-oncogenic enhancer network in inflammation-induced metaplastic progenitor cells to initiate pancreatic cancer
Yong LiYi HeJunya PengZhendong SuZeyao LiBingjie ZhangJing MaMeilian ZhuoDi ZouLiu Xin-deXinhong LiuWenze WangDan HuangMengyue XuJianbin WangHaiteng DengJing XueWei XieXun LanMo ChenYupei ZhaoWenming WuCharles J. David
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Pancreatic Intraepithelial Neoplasia
Activating mutations in the KRAS proto-oncogene occur almost ubiquitously in pancreatic ductal adenocarcinoma (PDAC) and in its putative precursor lesions, pancreatic intraepithelial neoplasia (PanIN). Conditional expression of an activated Kras allele in the mouse pancreas produces a model that faithfully recapitulates PanIN formation and progression to PDAC. Importantly, although nearly every cell in the pancreata of these mice express activated Kras, only a very small minority of cells give rise to PanINs. How the transforming activity of Kras is constrained in the pancreas remains unknown, and the cell types from which PanINs and PDAC arise are similarly unknown. Here, we describe our recent results demonstrating that acinar cells are competent to form Kras-induced PanINs, and that active Notch signaling can synergize with Kras in PanIN initiation and progression. Further efforts to understand how Notch and Kras synergize, as well as experiments to determine how other pancreatic cell types contribute to PDAC development, should aid in the development of new therapies and early detection techniques that are desperately needed for this cancer.
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Abstract Pancreatic cancer is characterized by the prevalence of oncogenic mutations in KRAS. Previous studies have reported that altered KRAS gene dosage drives progression and metastasis in pancreatic cancer. While the role of oncogenic KRAS mutations is well characterized, the relevance of the partnering wild-type KRAS allele in pancreatic cancer is less well understood and controversial. Using in vivo mouse modelling of pancreatic cancer, we demonstrated that wild-type KRAS restrains the oncogenic impact of mutant KRAS and dramatically impacts both KRAS-mediated tumorigenesis and therapeutic response. Mechanistically, deletion of wild-type Kras increased oncogenic KRAS signaling through the downstream MAPK effector pathway, driving pancreatic intraepithelial neoplasia (PanIN) initiation. In addition, in the KPC mouse model, a more aggressive model of pancreatic cancer, lack of wild-type KRAS led to accelerated initiation but delayed tumor progression. These tumors had altered stroma and an enrichment of immunogenic gene signatures. Importantly, loss of wild-type Kras sensitized Kras mutant tumors to MEK1/2 inhibition though tumors eventually became resistant and then rapidly progressed. This study demonstrates the repressive role of wild-type KRAS during pancreatic tumorigenesis and highlights the critical impact of the presence of wild-type KRAS in both tumor progression and therapeutic response in pancreatic cancer.
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Abstract Pancreatic cancer is characterised by the prevalence of oncogenic mutations in KRAS . Previous studies have reported that altered Kras gene dosage drives progression and metastatic incidence in pancreatic cancer. While the role of oncogenic KRAS mutation is well characterised, the relevance of the partnering wild-type KRAS allele in pancreatic cancer is less well understood and controversial. Using in vivo mouse modelling of pancreatic cancer, we demonstrate that wild-type Kras restrains the oncogenic impact of mutant Kras , and drastically impacts both Kras -mediated tumourigenesis and therapeutic response. Mechanistically, deletion of wild-type Kras increases oncogenic Kras signalling through the downstream MAPK effector pathway, driving pancreatic intraepithelial neoplasia (PanIN) initiation. In addition, in the KPC mouse model, a more aggressive model of pancreatic cancer, loss of wild-type KRAS leads to accelerated initiation but delayed tumour progression. These tumours had altered stroma, downregulated Myc levels and an enrichment for immunogenic gene signatures. Importantly, loss of wild-type Kras sensitises Kras mutant tumours to MEK1/2 inhibition though tumours eventually become resistant and then rapidly progress. This study demonstrates the repressive role of wild-type Kras during pancreatic tumourigenesis and highlights the critical impact of the presence of wild-type KRAS on tumourigenesis and therapeutic response in pancreatic cancer.
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Pancreatic ductal adenocarcinoma (PDAC) is one of the leading forms of cancer related deaths in the United States. With limited treatment options and unreliable diagnostic methods, long-term survival rates following a diagnosis of pancreatic cancer remain poor. Pancreatic intraepithelial neoplasia (PanIN) are precancerous lesions that precede progression towards PDAC. PanIN occur in increasing complexity as the disease progresses and the description of PanIN plays a critical role in describing, staging and diagnosing PDAC. Inconsistencies in PanIN classifications exist even amongst leading pathologists. This has led to debate and confusion among researchers and pathologists involved in pancreatic cancer research, diagnosis and treatment. We have sought to initiate a discussion with leading pathologists with a goal of increasing consensus in the interpretation of PanIN and associated structures within the precancerous pancreas. Toward achieving this goal, we are in the process of conducting an extensive study of over 1000 male and female pancreata in varying stages of PanIN progression isolated from the Ptf1aCre/+;LSL-KrasG12D/+ transgenic mouse model of pancreatic cancer. Using this extensive database, we have established the Mouse Model of Pancreatic Cancer Atlas (MMPCA) to serve as a platform for meaningful and interactive discussion among researchers and pathologists who study pancreatic disease. We hope that the MMPCA will be an effective tool for promoting a more consistent and accurate consensus of PanIN classifications in the future.
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Pancreatic cancer is a human malignancy with one of the highest mortality rates and little progress has been achieved in its treatment in recent decades. Further improvement to the understanding of the biological and molecular mechanisms underlying the initiation and development of pancreatic ductal adenocarcinoma (PDAC) is required. Previous studies using genetically engineered mouse models have demonstrated that oncogenic GTPase KRas (KRAS) mutation is involved in the formation of pancreatic intraepithelial neoplasia and promotes the progression of PDAC. However, attempts to target KRAS directly by pharmacological inhibition have been unsuccessful. This has resulted in increased efforts to identify pharmacological targets and nodes associated with the mutated KRAS. The present review discusses the recent progress and prospects of KRAS signaling in pancreatic cancer.
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Pancreatic cancer is one of the deadliest human malignancies and little progress has been achieved in its treatment over the past decades. Advances in our understanding of the biology of this disease provide new potential opportunities for treatment. Pancreatic cancer is preceded by precursor lesions, the most common of which are known as Pancreatic Intraepithelial Neoplasia (PanIN). PanIN lesions, which are the focus of this review, have a high incidence of Kras mutations, and Kras mutations are a hallmark of the late-stage disease. We now know from genetically engineered mouse models that oncogenic Kras is not only driving the formation of pancreatic cancer precursor lesions, but it is also required for their progression, and for the maintenance of invasive and metastatic disease. Thus, an enormous effort is being placed in generating Kras inhibitors for clinical use. Additionally, alternative approaches, including understanding the role of Kras effector pathways at different stages of the disease progression, are being devised to target Kras effector pathways therapeutically. In particular, efforts have focused on the MAPK pathway and the PI3K pathway, for which inhibitors are widely available. Finally, recent studies have highlighted the need for oncogenic Kras to establish feedback mechanisms that maintain its levels of activity; the latter might constitute alternative ways to target Kras in pancreatic cancer. Here, we will review recent basic research and discuss potential therapeutic applications.
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Abstract Chronic or repeated episodes of acute pancreatic inflammation, or pancreatitis, are risk factors for the development of pancreatic cancer. Pancreatic cancer is characterized by a strong fibro‐inflammatory tumor microenvironment. In pancreatitis, the same fibro‐inflammatory reaction is observed concurrently with a loss of normal pancreatic cells. Mouse models are commonly employed to study the progression of pancreatitis and pancreatic cancer, with genetic and pharmacological tools used to elucidate cellular and acellular interactions within pancreatic tumors. Described in this article is a protocol for using Kras G12D ; Pdx1‐Cre (KC) mice stimulated with caerulein, a small oligopeptide that increases secretion of digestive enzymes, as a model for pancreatitis. KRAS is mutated in 90‐95% of the tumors in patients with pancreatic cancer. The combination of this mutation with an inflammatory stimulus accelerates the development of pancreatic cancer. The protocol detailed in this report follows the progression of disease in KC mice from pancreatic intraepithelial neoplasias to invasive pancreatic adenocarcinoma. © 2018 by John Wiley & Sons, Inc.
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Abstract Pancreatic cancer is one of the most aggressive cancers and has an extremely poor prognosis. Despite recent progress in both basic and clinical research, most pancreatic cancers are detected at an incurable stage owing to the absence of disease-specific symptoms. Thus, developing novel approaches for detecting pancreatic cancer at an early stage is imperative. Our in silico and immunohistochemical analyses showed that KIAA1199 is specifically expressed in human pancreatic cancer cells and pancreatic intraepithelial neoplasia, the early lesion of pancreatic cancer, in a genetically engineered mouse model and in human patient samples. We also detected secreted KIAA1199 protein in blood samples obtained from pancreatic cancer mouse models, but not in normal mice. Furthermore, we found that assessing KIAA1199 autoantibody increased the sensitivity of detecting pancreatic cancer. These results indicate the potential benefits of using KIAA1199 as a biomarker for early-stage pancreatic cancer.
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