Zebrafish reporter lines reveal in vivo signaling pathway activities involved in pancreatic cancer
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...
| Main Authors: | , , , , , , , , , |
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| Format: | Article |
| Language: | English |
| Published: |
The Company of Biologists
2014-07-01
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| Series: | Disease Models & Mechanisms |
| Subjects: | |
| Online Access: | http://dmm.biologists.org/content/7/7/883 |
| _version_ | 1818991545212207104 |
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| author | Marco Schiavone Elena Rampazzo Alessandro Casari Giusy Battilana Luca Persano Enrico Moro Shu Liu Steve D. Leach Natascia Tiso Francesco Argenton |
| author_facet | Marco Schiavone Elena Rampazzo Alessandro Casari Giusy Battilana Luca Persano Enrico Moro Shu Liu Steve D. Leach Natascia Tiso Francesco Argenton |
| author_sort | Marco Schiavone |
| collection | DOAJ |
| description | 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. |
| first_indexed | 2024-12-20T20:11:58Z |
| format | Article |
| id | doaj.art-97164d1965eb48629a8ca60691ca70c9 |
| institution | Directory Open Access Journal |
| issn | 1754-8403 1754-8411 |
| language | English |
| last_indexed | 2024-12-20T20:11:58Z |
| publishDate | 2014-07-01 |
| publisher | The Company of Biologists |
| record_format | Article |
| series | Disease Models & Mechanisms |
| spelling | doaj.art-97164d1965eb48629a8ca60691ca70c92022-12-21T19:27:49ZengThe Company of BiologistsDisease Models & Mechanisms1754-84031754-84112014-07-017788389410.1242/dmm.014969014969Zebrafish reporter lines reveal in vivo signaling pathway activities involved in pancreatic cancerMarco SchiavoneElena RampazzoAlessandro CasariGiusy BattilanaLuca PersanoEnrico MoroShu LiuSteve D. LeachNatascia TisoFrancesco ArgentonPancreatic 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.http://dmm.biologists.org/content/7/7/883ZebrafishPancreatic adenocarcinomaMedulloblastomaKRASReportersTGFβNotchShh |
| spellingShingle | Marco Schiavone Elena Rampazzo Alessandro Casari Giusy Battilana Luca Persano Enrico Moro Shu Liu Steve D. Leach Natascia Tiso Francesco Argenton Zebrafish reporter lines reveal in vivo signaling pathway activities involved in pancreatic cancer Disease Models & Mechanisms Zebrafish Pancreatic adenocarcinoma Medulloblastoma KRAS Reporters TGFβ Notch Shh |
| title | Zebrafish reporter lines reveal in vivo signaling pathway activities involved in pancreatic cancer |
| title_full | Zebrafish reporter lines reveal in vivo signaling pathway activities involved in pancreatic cancer |
| title_fullStr | Zebrafish reporter lines reveal in vivo signaling pathway activities involved in pancreatic cancer |
| title_full_unstemmed | Zebrafish reporter lines reveal in vivo signaling pathway activities involved in pancreatic cancer |
| title_short | Zebrafish reporter lines reveal in vivo signaling pathway activities involved in pancreatic cancer |
| title_sort | zebrafish reporter lines reveal in vivo signaling pathway activities involved in pancreatic cancer |
| topic | Zebrafish Pancreatic adenocarcinoma Medulloblastoma KRAS Reporters TGFβ Notch Shh |
| url | http://dmm.biologists.org/content/7/7/883 |
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