Mammals express four Notch receptor paralogs (Notchi -4) that have been implicated in a broad range of functions during embryogenesis, post-natal development, and vartous pathologies, including cancer. As a result, there is growing interest in therapies aimed at blocking or activating Notch signaling in specific cellular or pathological contexts. During the previous funding period, we explored the spectrum of effects triggered by loss of Notchi activity with a novel genetic approach combining a knock-in Notchi allele (Nl ::CreLo), in which Cre replaced the NICD, and a conditional Notchi target allele (Niflox). The trans-heterozygous animals (Nl :CreLo/flox) were bred to reporter mice developed in the Molecular Reporter Core which contained floxed-stop click beetle red luciferase and dual reporter (lac-Z or eYFP) genes on respective alleles downstream ofthe ROSA26 locus. A systematic, life-long in vivo screen with bioluminescence imaging of animals wherein a random, progressive and age-dependent Notchi loss occurred identified a role for Notchi in suppressing neoplasia ofthe vascular system. Our findings caution against the Genetech approach of therapies targeting Notchi and provide a model in which to assess strategies to delay, prevent or control vascular tumor formation and thereby widen the therapeutic window of anti-Notch therapies. We will examine age, diet and organ dependence in vascular tumor formation using new Nl ::CreERT2 alleles permitting temporal control over loss of Notchi. We will use another new Notch trans-heterozygous combination, N2::CreLo/flox, to monitor risks associated specifically with loss of Notch2. An additional benefit from the proposed experiments will be a detailed map of all stem cell compartments where Notchi and Notch2 maintain stemness or promote differentiation. These studies will ultimately lead to safer Notch- targeting therapies.

Public Health Relevance

Unique trans-heterozygous animals (N1/2:CreLo/flox) bred to molecular imaging reporter mice will be used for life-long in vivo screens with bioluminescence imaging and MRI to study age-dependent roles for Notch in suppressing neoplasias of the vascular system.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Specialized Center (P50)
Project #
2P50CA094056-12
Application #
8195495
Study Section
Special Emphasis Panel (ZCA1-SRLB-9 (M1))
Project Start
2012-01-01
Project End
2016-12-31
Budget Start
2012-08-27
Budget End
2012-12-31
Support Year
12
Fiscal Year
2012
Total Cost
$119,281
Indirect Cost
Name
Washington University
Department
Type
DUNS #
068552207
City
Saint Louis
State
MO
Country
United States
Zip Code
63130
Pisaneschi, Federica; Kelderhouse, Lindsay E; Hardy, Amanda et al. (2017) Automated, Resin-Based Method to Enhance the Specific Activity of Fluorine-18 Clicked PET Radiotracers. Bioconjug Chem 28:583-589
Zhu, Zhe; Gorman, Matthew J; McKenzie, Lisa D et al. (2017) Zika virus has oncolytic activity against glioblastoma stem cells. J Exp Med 214:2843-2857
Zhang, Daoxiang; Li, Lin; Jiang, Hongmei et al. (2017) Constitutive IRAK4 Activation Underlies Poor Prognosis and Chemoresistance in Pancreatic Ductal Adenocarcinoma. Clin Cancer Res 23:1748-1759
Lu, Zhi Hong; Kaliberov, Sergey; Sohn, Rebecca E et al. (2017) A new model of multi-visceral and bone metastatic prostate cancer with perivascular niche targeting by a novel endothelial specific adenoviral vector. Oncotarget 8:12272-12289
Miller, Jessica; Wang, Steven T; Orukari, Inema et al. (2017) Perfusion-based fluorescence imaging method delineates diverse organs and identifies multifocal tumors using generic near-infrared molecular probes. J Biophotonics :
Miller, Jessica P; Habimana-Griffin, LeMoyne; Edwards, Tracy S et al. (2017) Multimodal fluorescence molecular imaging for in vivo characterization of skin cancer using endogenous and exogenous fluorophores. J Biomed Opt 22:66007
Zacharias, Niki Marie; McCullough, Christopher; Shanmugavelandy, Sriram et al. (2017) Metabolic Differences in Glutamine Utilization Lead to Metabolic Vulnerabilities in Prostate Cancer. Sci Rep 7:16159
Gilson, Rebecca C; Black, Kvar C L; Lane, Daniel D et al. (2017) Hybrid TiO2 -Ruthenium Nano-photosensitizer Synergistically Produces Reactive Oxygen Species in both Hypoxic and Normoxic Conditions. Angew Chem Int Ed Engl 56:10717-10720
Tang, Rui; Habimana-Griffin, LeMoyne M; Lane, Daniel D et al. (2017) Nanophotosensitive drugs for light-based cancer therapy: what does the future hold? Nanomedicine (Lond) 12:1101-1105
Miller, Jessica P; Maji, Dolonchampa; Lam, Jesse et al. (2017) Noninvasive depth estimation using tissue optical properties and a dual-wavelength fluorescent molecular probe in vivo. Biomed Opt Express 8:3095-3109

Showing the most recent 10 out of 273 publications