Differential in vivo tumorigenicity of diverse KRAS mutations in vertebrate pancreas: A comprehensive survey

Differential in vivo tumorigenicity of diverse KRAS mutations in vertebrate pancreas: A comprehensive survey

Somatic activation of the KRAS proto-oncogene is evident in almost all pancreatic cancers, and appears to represent an initiating event. These mutations occur primarily at codon 12 and less frequently at codons 13 and 61. While some studies have suggested that different KRAS mutations may have varia...

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Main Authors: Park, Joon Tae, Johnson, Nicole, Liu, Shu, Levesque, Mathieu, Wang, Yue J., Ho, Hao, Huso, David, Maitra, Anirban, Parsons, Michael J., Prescott, Jason D., Leach, Steven D.
Format: Online
Language:English
Published: 2014
Online Access:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4836617/
id pubmed-4836617
recordtype oai_dc
spelling pubmed-48366172016-04-19 Differential in vivo tumorigenicity of diverse KRAS mutations in vertebrate pancreas: A comprehensive survey Park, Joon Tae Johnson, Nicole Liu, Shu Levesque, Mathieu Wang, Yue J. Ho, Hao Huso, David Maitra, Anirban Parsons, Michael J. Prescott, Jason D. Leach, Steven D. Article Somatic activation of the KRAS proto-oncogene is evident in almost all pancreatic cancers, and appears to represent an initiating event. These mutations occur primarily at codon 12 and less frequently at codons 13 and 61. While some studies have suggested that different KRAS mutations may have variable oncogenic properties, to date there has been no comprehensive functional comparison of multiple KRAS mutations in an in vivo vertebrate tumorigenesis system. We generated a Gal4/UAS-based zebrafish model of pancreatic tumorigenesis in which the pancreatic expression of UAS-regulated oncogenes is driven by a ptf1a:Gal4-VP16 driver line. This system allowed us to rapidly compare the ability of 12 different KRAS mutations (G12A, G12C, G12D, G12F, G12R, G12S, G12V, G13C, G13D, Q61L, Q61R, and A146T) to drive pancreatic tumorigenesis in vivo. Among fish injected with one of five KRAS mutations reported in other tumor types but not in human pancreatic cancer, 2/79 (0.25%) developed pancreatic tumors, with both tumors arising in fish injected with A146T. In contrast, among fish injected with one of seven KRAS mutations known to occur in human pancreatic cancer, 22/106 (20.8%) developed pancreatic cancer. All eight tumorigenic KRAS mutations were associated with downstream MAPK/ERK pathway activation in preneoplastic pancreatic epithelium, while non-tumorigenic mutations were not. These results suggest that the spectrum of KRAS mutations observed in human pancreatic cancer reflects selection based upon variable tumorigenic capacities, including the ability to activate MAPK/ERK signaling. 2014-07-28 2015-05-21 /pmc/articles/PMC4836617/ /pubmed/25065594 http://dx.doi.org/10.1038/onc.2014.223 Text en http://www.nature.com/authors/editorial_policies/license.html#terms Users may view, print, copy, and download text and data-mine the content in such documents, for the purposes of academic research, subject always to the full Conditions of use:http://www.nature.com/authors/editorial_policies/license.html#terms
repository_type Open Access Journal
institution_category Foreign Institution
institution US National Center for Biotechnology Information
building NCBI PubMed
collection Online Access
language English
format Online
author Park, Joon Tae
Johnson, Nicole
Liu, Shu
Levesque, Mathieu
Wang, Yue J.
Ho, Hao
Huso, David
Maitra, Anirban
Parsons, Michael J.
Prescott, Jason D.
Leach, Steven D.
spellingShingle Park, Joon Tae
Johnson, Nicole
Liu, Shu
Levesque, Mathieu
Wang, Yue J.
Ho, Hao
Huso, David
Maitra, Anirban
Parsons, Michael J.
Prescott, Jason D.
Leach, Steven D.
Differential in vivo tumorigenicity of diverse KRAS mutations in vertebrate pancreas: A comprehensive survey
author_facet Park, Joon Tae
Johnson, Nicole
Liu, Shu
Levesque, Mathieu
Wang, Yue J.
Ho, Hao
Huso, David
Maitra, Anirban
Parsons, Michael J.
Prescott, Jason D.
Leach, Steven D.
author_sort Park, Joon Tae
title Differential in vivo tumorigenicity of diverse KRAS mutations in vertebrate pancreas: A comprehensive survey
title_short Differential in vivo tumorigenicity of diverse KRAS mutations in vertebrate pancreas: A comprehensive survey
title_full Differential in vivo tumorigenicity of diverse KRAS mutations in vertebrate pancreas: A comprehensive survey
title_fullStr Differential in vivo tumorigenicity of diverse KRAS mutations in vertebrate pancreas: A comprehensive survey
title_full_unstemmed Differential in vivo tumorigenicity of diverse KRAS mutations in vertebrate pancreas: A comprehensive survey
title_sort differential in vivo tumorigenicity of diverse kras mutations in vertebrate pancreas: a comprehensive survey
description Somatic activation of the KRAS proto-oncogene is evident in almost all pancreatic cancers, and appears to represent an initiating event. These mutations occur primarily at codon 12 and less frequently at codons 13 and 61. While some studies have suggested that different KRAS mutations may have variable oncogenic properties, to date there has been no comprehensive functional comparison of multiple KRAS mutations in an in vivo vertebrate tumorigenesis system. We generated a Gal4/UAS-based zebrafish model of pancreatic tumorigenesis in which the pancreatic expression of UAS-regulated oncogenes is driven by a ptf1a:Gal4-VP16 driver line. This system allowed us to rapidly compare the ability of 12 different KRAS mutations (G12A, G12C, G12D, G12F, G12R, G12S, G12V, G13C, G13D, Q61L, Q61R, and A146T) to drive pancreatic tumorigenesis in vivo. Among fish injected with one of five KRAS mutations reported in other tumor types but not in human pancreatic cancer, 2/79 (0.25%) developed pancreatic tumors, with both tumors arising in fish injected with A146T. In contrast, among fish injected with one of seven KRAS mutations known to occur in human pancreatic cancer, 22/106 (20.8%) developed pancreatic cancer. All eight tumorigenic KRAS mutations were associated with downstream MAPK/ERK pathway activation in preneoplastic pancreatic epithelium, while non-tumorigenic mutations were not. These results suggest that the spectrum of KRAS mutations observed in human pancreatic cancer reflects selection based upon variable tumorigenic capacities, including the ability to activate MAPK/ERK signaling.
publishDate 2014
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4836617/
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