PUBLICATION
Zebrafish reporter lines reveal in vivo signaling pathway activities involved in pancreatic cancer
- Authors
- Schiavone, M., Rampazzo, E., Casari, A., Battilana, G., Persano, L., Moro, E., Liu, S., Leach, S.D., Tiso, N., Argenton, F.
- ID
- ZDB-PUB-140601-6
- Date
- 2014
- Source
- Disease models & mechanisms 7(7): 883-94 (Journal)
- Registered Authors
- Argenton, Francesco, Casari, Alessandro, Leach, Steven D., Moro, Enrico, Schiavone, Marco, Tiso, Natascia
- Keywords
- none
- MeSH Terms
-
- Adenocarcinoma/genetics
- Adenocarcinoma/pathology
- Animals
- Animals, Genetically Modified
- Apoptosis/genetics
- Biomarkers/metabolism
- Cell Proliferation
- Cell Transformation, Neoplastic/genetics
- Cell Transformation, Neoplastic/pathology
- Disease Models, Animal
- Disease Progression
- Epithelial-Mesenchymal Transition/genetics
- Gene Expression Regulation, Neoplastic
- Genes, Reporter*
- Green Fluorescent Proteins/metabolism
- Kaplan-Meier Estimate
- Medulloblastoma/pathology
- Mutant Proteins/metabolism
- Organ Specificity
- Pancreatic Neoplasms/genetics*
- Pancreatic Neoplasms/pathology*
- Promoter Regions, Genetic/genetics
- Proto-Oncogene Proteins p21(ras)
- Signal Transduction*
- Transcription Factors/genetics
- Zebrafish/genetics*
- Zebrafish Proteins/metabolism
- PubMed
- 24878567 Full text @ Dis. Model. Mech.
Citation
Schiavone, M., Rampazzo, E., Casari, A., Battilana, G., Persano, L., Moro, E., Liu, S., Leach, S.D., Tiso, N., Argenton, F. (2014) Zebrafish reporter lines reveal in vivo signaling pathway activities involved in pancreatic cancer. Disease models & mechanisms. 7(7):883-94.
Abstract
Pancreatic adenocarcinoma, one of the worst malignancies of the exocrine pancreas, is a solid tumor with increasing incidence
and mortality in industrialized countries. This condition is usually driven by oncogenic KRAS point mutations and evolves into a highly aggressive metastatic carcinoma due to secondary gene mutations and unbalanced
expression of genes involved in the specific signaling pathways. To examine in vivo the effects of KRASG12D during pancreatic cancer progression and time correlation with cancer signaling pathway activities, we have generated a zebrafish
model of pancreatic adenocarcinoma in which eGFP-KRASG12D expression was specifically driven to the pancreatic tissue by using the GAL4/UAS conditional expression system. Outcrossing
the inducible oncogenic KRASG12D line with transgenic zebrafish reporters, harboring specific signaling responsive elements of transcriptional effectors,
we were able to follow TGFβ, Notch, Bmp and Shh activities during tumor development. Zebrafish transgenic lines expressing
eGFP-KRASG12D showed normal exocrine pancreas development until 3 weeks post fertilization (wpf). From 4 to 24 wpf we observed several
degrees of acinar lesions, characterized by an increase in mesenchymal cells and mixed acinar/ductal features, followed by
progressive bowel and liver infiltrations and, finally, highly aggressive carcinoma. Moreover, live imaging analysis of the
exocrine pancreatic tissue revealed an increasing number of KRAS-positive cells and progressive activation of TGFβ and Notch
pathways. Increase in TGFβ, following KRASG12D activation, was confirmed in a concomitant model of medulloblastoma (MDB). Notch and Shh signaling activities during tumor
onset were different between MDB and pancreatic adenocarcinoma, indicating a tissue-specific regulation of cell signaling
pathways. Moreover, our results show that a living model of pancreatic adenocarcinoma joined with cell signaling reporters
is a suitable tool for describing in vivo the signaling cascades and molecular mechanisms involved in tumor development and a potential platform to screen for novel
oncostatic drugs.
Genes / Markers
Expression
Phenotype
Mutations / Transgenics
Human Disease / Model
Sequence Targeting Reagents
Fish
Orthology
Engineered Foreign Genes
Mapping