ArticlePloS one2013
Loss of canonical Smad4 signaling promotes KRAS driven malignant transformation of human pancreatic duct epithelial cells and metastasis.
Article in PloS one, 2013. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 21 papers.
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Who cites it
21 citing papers in PubMed, 34 citations in OpenAlex.
- Twist1 overexpression models an aggressive subtype of pancreatic ductal adenocarcinoma in vivo.Lab animal · 2026Article
- The TGF-β superfamily as potential therapeutic targets in pancreatic cancer.Frontiers in oncology · 2024Review
- NF1 loss of function as an alternative initiating event in pancreatic ductal adenocarcinoma.Cell reports · 2022Article
- Identification of LIPH as an unfavorable biomarkers correlated with immune suppression or evasion in pancreatic cancer based on RNA-seq.Cancer immunology, immunotherapy : CII · 2022Article
- TGFβ Signaling in the Pancreatic Tumor Microenvironment.Cancers · 2021Review
- Loss of Smad4 promotes aggressive lung cancer metastasis by de-repression of PAK3 via miRNA regulation.Nature communications · 2021Article
- Review
- TGF-β Signaling in Liver, Pancreas, and Gastrointestinal Diseases and Cancer.Gastroenterology · 2021Review
- Article
- The Role of TGF-β and Its Receptors in Gastrointestinal Cancers.Translational oncology · 2019Review
- Roles of Smads Family and Alternative Splicing Variants of Smad4 in Different Cancers.Journal of Cancer · 2018Review
- Development of Aggressive Pancreatic Ductal Adenocarcinomas Depends on Granulocyte Colony Stimulating Factor Secretion in Carcinoma Cells.Cancer immunology research · 2017Article
- The TGF-β/Smad4 Signaling Pathway in Pancreatic Carcinogenesis and Its Clinical Significance.Journal of clinical medicine · 2017Review
- TGF-β in pancreatic cancer initiation and progression: two sides of the same coin.Cell & bioscience · 2017Review
- SMAD4 loss enables EGF, TGFβ1 and S100A8/A9 induced activation of critical pathways to invasion in human pancreatic adenocarcinoma cells.Oncotarget · 2016Article
- TGF-β signaling in liver and gastrointestinal cancers.Cancer letters · 2016Review
- Article
- The P2X7 receptor regulates cell survival, migration and invasion of pancreatic ductal adenocarcinoma cells.Molecular cancer · 2015Article
- Coiled-coil domain containing 68 (CCDC68) demonstrates a tumor-suppressive role in pancreatic ductal adenocarcinoma.Oncogene · 2015Article
- SMAD4 and its role in pancreatic cancer.Tumour biology : the journal of the International Society for Oncodevelopmental Biology and Medicine · 2015Review
Corrections and comments
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Authors and funding
7 authors at 3 institutions in 1 country.
Funding
Abstract
Pancreatic ductal adenocarcinoma (PDAC) is the fourth most common cause of cancer death in North America. Activating KRAS mutations and Smad4 loss occur in approximately 90% and 55% of PDAC, respectively. While their roles in the early stages of PDAC development have been confirmed in genetically modified mouse models, their roles in the multistep malignant transformation of human pancreatic duct cells have not been directly demonstrated. Here, we report that Smad4 represents a barrier in KRAS-mediated malignant transformation of the near normal immortalized human pancreatic duct epithelial (HPDE) cell line model. Marked Smad4 downregulation by shRNA in KRAS (G12V) expressing HPDE cells failed to cause tumorigenic transformation. However, KRAS-mediated malignant transformation occurred in a new HPDE-TGF-β resistant (TβR) cell line that completely lacks Smad4 protein expression and is resistant to the mito-inhibitory activity of TGF-β. This transformation resulted in tumor formation and development of metastatic phenotype when the cells were implanted orthotopically into the mouse pancreas. Smad4 restoration re-established TGF-β sensitivity, markedly increased tumor latency by promoting apoptosis, and decreased metastatic potential. These results directly establish the critical combination of the KRAS oncogene and complete Smad4 inactivation in the multi-stage malignant transformation and metastatic progression of normal human HPDE cells.
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.