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• W4361948688 abstract "<div>Abstract<p><b>Purpose:</b> Aberrant activation of the Notch signaling pathway is commonly observed in human pancreatic cancer, although the mechanism(s) for this activation has not been elucidated.</p><p><b>Experimental Design:</b> A 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 <i>NOTCH1</i> or pharmacologically by means of the γ-secretase inhibitor GSI-18, was used for assessing requirement of Notch signaling in pancreatic cancer initiation and maintenance.</p><p><b>Results:</b> Striking overexpression of Notch ligand transcripts was detectable in the vast majority of pancreatic cancer cell lines, most prominently <i>JAGGED2</i> (18 of 20 cases, 90%) and <i>DLL4</i> (10 of 20 cases, 50%). In two cell lines, genomic amplification of the <i>DLL3</i> locus was observed, mirrored by overexpression of <i>DLL3</i> transcripts. In contrast, coding region mutations of <i>NOTCH1</i> or <i>NOTCH2</i> 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 <i>in vitro</i> and xenograft engraftment <i>in vivo</i>, underscoring a requirement for the Notch-dependent aldehyde dehydrogenase–expressing cells in pancreatic cancer initiation.</p><p><b>Conclusions:</b> Our 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.</p></div>" @default.
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• W4361948688 date "2023-03-31" @default.
• W4361948688 modified "2023-10-16" @default.
• W4361948688 title "Data from Ligand-dependent Notch Signaling Is Involved in Tumor Initiation and Tumor Maintenance in Pancreatic Cancer" @default.
• W4361948688 doi "https://doi.org/10.1158/1078-0432.c.6517347.v1" @default.
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