ArticleGastroenterology2016
Loss of Activin Receptor Type 1B Accelerates Development of Intraductal Papillary Mucinous Neoplasms in Mice With Activated KRAS.
Article in Gastroenterology, 2016. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 24 papers.
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Who cites it
24 citing papers in PubMed, 38 citations in OpenAlex.
- Loss of ALK4 promotes cancer progression through regulating TGF-β receptor N-glycosylation.Nature communications · 2025Article
- Review
- On the Effects of Gene Mutations in Pancreatic Tumorigenesis, Depending on the Cell Types and Times When They Are Induced.Cellular and molecular gastroenterology and hepatology · 2024Article
- Uncovering Tumor-Promoting Roles of Activin A in Pancreatic Ductal Adenocarcinoma.Advanced science (Weinheim, Baden-Wurttemberg, Germany) · 2023Article
- Clinical and Molecular Attributes and Evaluation of Pancreatic Cystic Neoplasm.Biochimica et biophysica acta. Reviews on cancer · 2023Review
- Inactivation ofCancer research communications · 2022Article
- Emerging Potential Mechanism and Therapeutic Target of Ferroptosis in PDAC: A Promising Future.International journal of molecular sciences · 2022Review
- Intraductal Papillary Mucinous Neoplasms of the Pancreas: A Review of Their Genetic Characteristics and Mouse Models.Cancers · 2021Review
- Dual Roles of the Activin Signaling Pathway in Pancreatic Cancer.Biomedicines · 2021Review
- Integrated Analysis of Cell Cycle-Related and Immunity-Related Biomarker Signatures to Improve the Prognosis Prediction of Lung Adenocarcinoma.Frontiers in oncology · 2021Article
- CFIm25-regulated lncRNA acv3UTR promotes gastric tumorigenesis via miR-590-5p/YAP1 axis.Oncogene · 2020Article
- Clinical assessment of the GNAS mutation status in patients with intraductal papillary mucinous neoplasm of the pancreas.Surgery today · 2019Review
- The Use of Genetically Engineered Mouse Models for Studying the Function of Mutated Driver Genes in Pancreatic Cancer.Journal of clinical medicine · 2019Review
- CRISPR-Cas9-mediated gene knockout in intestinal tumor organoids provides functional validation for colorectal cancer driver genes.Proceedings of the National Academy of Sciences of the United States of America · 2019Article
- Activin Receptor-Like Kinase 4 Haplodeficiency Mitigates Arrhythmogenic Atrial Remodeling and Vulnerability to Atrial Fibrillation in Cardiac Pathological Hypertrophy.Journal of the American Heart Association · 2018Article
- Pancreatic DCLK1Cancer letters · 2018Article
- Loss of Pten and Activation of Kras Synergistically Induce Formation of Intraductal Papillary Mucinous Neoplasia From Pancreatic Ductal Cells in Mice.Gastroenterology · 2018Article
- Exome-wide somatic mutation characterization of small bowel adenocarcinoma.PLoS genetics · 2018Article
- Cells of origin of pancreatic neoplasms.Surgery today · 2018Review
- Pancreatic Cancer: Molecular Characterization, Clonal Evolution and Cancer Stem Cells.Biomedicines · 2017Review
Corrections and comments
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Authors and funding
15 authors at 3 institutions in 1 country.
Funding
Abstract
BACKGROUND &
aimsActivin, a member of the transforming growth factor-β (TGFB) family, might be involved in pancreatic tumorigenesis, similar to other members of the TGFB family. Human pancreatic ductal adenocarcinomas contain somatic mutations in the activin A receptor type IB (ACVR1B) gene, indicating that ACVR1B could be a suppressor of pancreatic tumorigenesis.
methodsWe disrupted Acvr1b specifically in pancreata of mice (Acvr1b(flox/flox);Pdx1-Cre mice) and crossed them with LSL-KRAS(G12D) mice, which express an activated form of KRAS and develop spontaneous pancreatic tumors. The resulting Acvr1b(flox/flox);LSL-KRAS(G12D);Pdx1-Cre mice were monitored; pancreatic tissues were collected and analyzed by histology and immunohistochemical analyses. We also analyzed p16(flox/flox);LSL-Kras(G12D);Pdx1-Cre mice and Cre-negative littermates (controls). Genomic DNA, total RNA, and protein were isolated from mouse tissues and primary pancreatic tumor cell lines and analyzed by reverse-transcription polymerase chain reaction, sequencing, and immunoblot analyses. Human intraductal papillary mucinous neoplasm (IPMN) specimens were analyzed by immunohistochemistry.
resultsLoss of ACVR1B from pancreata of mice increased the proliferation of pancreatic epithelial cells, led to formation of acinar to ductal metaplasia, and induced focal inflammatory changes compared with control mice. Disruption of Acvr1b in LSL-KRAS(G12D);Pdx1-Cre mice accelerated the growth of pancreatic IPMNs compared with LSL-KRAS(G12D);Pdx1-Cre mice, but did not alter growth of pancreatic intraepithelial neoplasias. We associated perinuclear localization of the activated NOTCH4 intracellular domain to the apical cytoplasm of neoplastic cells with the expansion of IPMN lesions in Acvr1b(flox/flox);LSL-KRAS(G12D);Pdx1-Cre mice. Loss of the gene that encodes p16 (Cdkn2a) was required for progression of IPMNs to pancreatic ductal adenocarcinomas in Acvr1b(flox/flox);LSL-Kras(G12D);Pdx1-Cre mice. We also observed progressive loss of p16 in human IPMNs of increasing grades.
conclusionsLoss of ACVR1B accelerates growth of mutant KRAS-induced pancreatic IPMNs in mice; this process appears to involve NOTCH4 and loss of p16. ACVR1B suppresses early stages of pancreatic tumorigenesis; the activin signaling pathway therefore might be a therapeutic target for pancreatic cancer.
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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.