ArticleClinical cancer research : an official journal of the American Association for Cancer Research2009
Ligand-dependent Notch signaling is involved in tumor initiation and tumor maintenance in pancreatic cancer.
Article in Clinical cancer research : an official journal of the American Association for Cancer Research, 2009. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 104 papers.
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Who cites it
104 citing papers in PubMed, 196 citations in OpenAlex.
- A phase II study of the gamma secretase inhibitor RO4929097 in patients with previously treated metastatic pancreatic adenocarcinoma.Investigational new drugs · 2014Trial
- Circular RNA hsa_circ_0001829 promotes pancreatic ductal adenocarcinoma through miR-7113-3p/DTX4 axis.World journal of surgical oncology · 2026Article
- Primary cilia and cancer: a tale of many faces.Oncogene · 2025Review
- Targeting DLL3: Innovative Strategies for Tumor Treatment.Pharmaceutics · 2025Review
- CAR-T therapy for endocrine neoplasms: novel targets and combination of therapies.Frontiers in endocrinology · 2025Review
- Article
- Notch signaling pathway in cancer: from mechanistic insights to targeted therapies.Signal transduction and targeted therapy · 2024Review
- Investigating underlying molecular mechanisms, signaling pathways, emerging therapeutic approaches in pancreatic cancer.Frontiers in oncology · 2024Review
- DLL3 Is a Prognostic and Potentially Predictive Biomarker for Immunotherapy Linked to PD/PD-L Axis and NOTCH1 in Pancreatic Cancer.Biomedicines · 2023Article
- Krüppel-like factor 10 modulates stem cell phenotypes of pancreatic adenocarcinoma by transcriptionally regulating notch receptors.Journal of biomedical science · 2023Article
- The Intricate Notch Signaling Dynamics in Therapeutic Realms of Cancer.ACS pharmacology & translational science · 2023Review
- Jagged/Notch proteins promote endothelial-mesenchymal transition-mediated pulmonary arterial hypertension via upregulation of the expression of GATAs.Journal of cellular and molecular medicine · 2023Article
- Targeting the DLL/Notch Signaling Pathway in Cancer: Challenges and Advances in Clinical Development.Molecular cancer therapeutics · 2023Review
- Cuproptosis-related LncRNAs signature as biomarker of prognosis and immune infiltration in pancreatic cancer.Frontiers in genetics · 2023Article
- Inactivation ofCancer research communications · 2022Article
- Delta-like canonical Notch ligand 3 as a potential therapeutic target in malignancies: A brief overview.Cancer science · 2021Review
- A review: hippo signaling pathway promotes tumor invasion and metastasis by regulating target gene expression.Journal of cancer research and clinical oncology · 2021Review
- CDK5 positively regulates Notch1 signaling in pancreatic cancer cells by phosphorylation.Cancer medicine · 2021Article
- Pancreatic Cancer and Therapy: Role and Regulation of Cancer Stem Cells.International journal of molecular sciences · 2021Review
- From the perspective of Traditional Chinese Medicine: Treatment of mental disorders in COVID-19 survivors.Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie · 2020Review
44 more citing papers are in PubMed but not listed here.
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Authors and funding
10 authors at 3 institutions in 1 country.
Funding
Abstract
purposeAberrant activation of the Notch signaling pathway is commonly observed in human pancreatic cancer, although the mechanism(s) for this activation has not been elucidated. EXPERIMENTAL
designA panel of 20 human pancreatic cancer cell lines was profiled for the expression of Notch pathway-related ligands, receptors, and target genes. Disruption of intracellular Notch signaling, either genetically by RNA interference targeting NOTCH1 or pharmacologically by means of the gamma-secretase inhibitor GSI-18, was used for assessing requirement of Notch signaling in pancreatic cancer initiation and maintenance.
resultsStriking overexpression of Notch ligand transcripts was detectable in the vast majority of pancreatic cancer cell lines, most prominently JAGGED2 (18 of 20 cases, 90%) and DLL4 (10 of 20 cases, 50%). In two cell lines, genomic amplification of the DLL3 locus was observed, mirrored by overexpression of DLL3 transcripts. In contrast, coding region mutations of NOTCH1 or NOTCH2 were not observed. Genetic and pharmacologic inhibition of Notch signaling mitigated anchorage-independent growth in pancreatic cancer cells, confirming that sustained Notch activation is a requirement for pancreatic cancer maintenance. Further, transient pretreatment of pancreatic cancer cells with GSI-18 resulted in depletion in the proportion of tumor-initiating aldehyde dehydrogenase-expressing subpopulation and was associated with inhibition of colony formation in vitro and xenograft engraftment in vivo, underscoring a requirement for the Notch-dependent aldehyde dehydrogenase-expressing cells in pancreatic cancer initiation.
conclusionsOur studies confirm that Notch activation is almost always ligand dependent in pancreatic cancer, and inhibition of Notch signaling is a promising therapeutic strategy in this malignancy.
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