Cross-species analysis of genetically engineered mouse models of MAPK-driven colorectal cancer identifies hallmarks of the human disease

Belmont, P. J. et al. (2014) Cross-species analysis of genetically engineered mouse models of MAPK-driven colorectal cancer identifies hallmarks of the human disease. Disease Models and Mechanisms, 7(6), pp. 613-623. (doi:10.1242/dmm.013904)

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Publisher's URL: http://dx.doi.org/10.1242/dmm.013904

Abstract

Effective treatment options for advanced colorectal cancer (CRC) are limited, survival rates are poor and this disease continues to be a leading cause of cancer-related deaths worldwide. Despite being a highly heterogeneous disease, a large subset of individuals with sporadic CRC typically harbor relatively few established ‘driver’ lesions. Here, we describe a collection of genetically engineered mouse models (GEMMs) of sporadic CRC that combine lesions frequently altered in human patients, including well-characterized tumor suppressors and activators of MAPK signaling. Primary tumors from these models were profiled, and individual GEMM tumors segregated into groups based on their genotypes. Unique allelic and genotypic expression signatures were generated from these GEMMs and applied to clinically annotated human CRC patient samples. We provide evidence that a Kras signature derived from these GEMMs is capable of distinguishing human tumors harboring KRAS mutation, and tracks with poor prognosis in two independent human patient cohorts. Furthermore, the analysis of a panel of human CRC cell lines suggests that high expression of the GEMM Kras signature correlates with sensitivity to targeted pathway inhibitors. Together, these findings implicate GEMMs as powerful preclinical tools with the capacity to recapitulate relevant human disease biology, and support the use of genetic signatures generated in these models to facilitate future drug discovery and validation efforts.

Item Type:Articles
Status:Published
Refereed:Yes
Glasgow Author(s) Enlighten ID:Derkits, Ms Sahra and Sansom, Professor Owen
Authors: Belmont, P. J., Budinska, E., Jiang, P., Sinnamon, M. J., Coffee, E., Roper, J., Xie, T., Rejto, P. A., Derkits, S., Sansom, O. J., Delorenzi, M., Tejpar, S., Hung, K. E., and Martin, E. S.
College/School:College of Medical Veterinary and Life Sciences > Institute of Cancer Sciences
Journal Name:Disease Models and Mechanisms
Publisher:The Company of Biologists Ltd.
ISSN:1754-8403
ISSN (Online):1754-8411
Copyright Holders:Copyright © 2014 The Authors
First Published:First published in Disease Models and Mechanisms 7(6):613-623
Publisher Policy:Reproduced under a Creative Commons License

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