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| Status |
Public on Jul 27, 2020 |
| Title |
Effect of NOTCH-γ-secretase inhibitor LY3039478 therapy on patient derived xenograft (PDX) mouse model of intrahepatic cholangiocarcinoma |
| Organism |
Homo sapiens |
| Experiment type |
Expression profiling by array
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| Summary |
Intrahepatic Cholangiocarcinoma (iCCA) is a deadly disease with rising incidence and few treatment options. Recently, aberrant Notch signaling was reported in iCCA carcinogenesis. Specifically, altered expression and/or activation of the receptors Notch1/2 suggests a role for Notch pathway overactivation during iCCA formation and progression. In this study, we examined the effects of Notch inhibition by γ-secretase inhibitor, LY3039478 in human iCCA cell lines and in an excellent patient derived-xenograft (PDX) model. Expression of several Notch pathway components, including NICD, Hes1, and DLL4, were reduced after GSI treatment. Moreover, LY3039478 inhibits cell migration and invasion while in GSI-treated mice, tumor growth was delayed compared to vehicle and chemotherapy. These results support the notion that Notch inhibition by GSI may reduce in vivo tumorigenesis. In addition, GSI reduces in PDX model VEGFA and MMP13 involved in capillary tube formation and tumor progression. Here, we therefore show a link between the efficacy of Notch inhibition and the tumor microenvironment through LY3039478 that slows tumor progression compared to control mice blocking angiogenesis via MMP13 downregulation.
We used microarray technology to understand the molecular mechanisms affected by LY3039478. Cholangiocarcinoma PDX model was employed in this analysis.
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| Overall design |
Expression profiling of patient-derived xenografts (PDX) from patients with intrahepatic cholangiocarcinoma after and before LY3039478 treatment. Moreover, we also analyzed the of the original tumor mass and PDX tissue comparing them to the surrounding normal mass of patient.
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| Contributor(s) |
Mancarella S, Serino G, Giannelli G |
| Citation(s) |
32042099 |
| |
| Submission date |
Jul 10, 2019 |
| Last update date |
Jul 27, 2020 |
| Contact name |
Grazia Serino |
| E-mail(s) |
grazia.serino@irccsdebellis.it
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| Organization name |
National Institute of Gastroenterology “S. de Bellis”, Research Hospital
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| Street address |
Via Turi, 27
|
| City |
Castellana Grotte (BA) |
| ZIP/Postal code |
70013 |
| Country |
Italy |
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| Platforms (1) |
| GPL17586 |
[HTA-2_0] Affymetrix Human Transcriptome Array 2.0 [transcript (gene) version] |
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| Samples (11)
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| Relations |
| BioProject |
PRJNA553805 |
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