Cross-species analysis of genetically engineered mouse models of MAPK-driven colorectal cancer identifies hallmarks of the human disease
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 re...
| Main Authors: | , , , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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The Company of Biologists
2014-06-01
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| Series: | Disease Models & Mechanisms |
| Subjects: | |
| Online Access: | http://dmm.biologists.org/content/7/6/613 |
| _version_ | 1818900655503310848 |
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| author | Peter J. Belmont Eva Budinska Ping Jiang Mark J. Sinnamon Erin Coffee Jatin Roper Tao Xie Paul A. Rejto Sahra Derkits Owen J. Sansom Mauro Delorenzi Sabine Tejpar Kenneth E. Hung Eric S. Martin |
| author_facet | Peter J. Belmont Eva Budinska Ping Jiang Mark J. Sinnamon Erin Coffee Jatin Roper Tao Xie Paul A. Rejto Sahra Derkits Owen J. Sansom Mauro Delorenzi Sabine Tejpar Kenneth E. Hung Eric S. Martin |
| author_sort | Peter J. Belmont |
| collection | DOAJ |
| description | 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. |
| first_indexed | 2024-12-19T20:07:19Z |
| format | Article |
| id | doaj.art-5fd786955d0a4452bc283d40149f13df |
| institution | Directory Open Access Journal |
| issn | 1754-8403 1754-8411 |
| language | English |
| last_indexed | 2024-12-19T20:07:19Z |
| publishDate | 2014-06-01 |
| publisher | The Company of Biologists |
| record_format | Article |
| series | Disease Models & Mechanisms |
| spelling | doaj.art-5fd786955d0a4452bc283d40149f13df2022-12-21T20:07:26ZengThe Company of BiologistsDisease Models & Mechanisms1754-84031754-84112014-06-017661362310.1242/dmm.013904013904Cross-species analysis of genetically engineered mouse models of MAPK-driven colorectal cancer identifies hallmarks of the human diseasePeter J. BelmontEva BudinskaPing JiangMark J. SinnamonErin CoffeeJatin RoperTao XiePaul A. RejtoSahra DerkitsOwen J. SansomMauro DelorenziSabine TejparKenneth E. HungEric S. MartinEffective 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.http://dmm.biologists.org/content/7/6/613KRASBRAFMAPKColorectal cancerGEMMGenomic signatures |
| spellingShingle | Peter J. Belmont Eva Budinska Ping Jiang Mark J. Sinnamon Erin Coffee Jatin Roper Tao Xie Paul A. Rejto Sahra Derkits Owen J. Sansom Mauro Delorenzi Sabine Tejpar Kenneth E. Hung Eric S. Martin Cross-species analysis of genetically engineered mouse models of MAPK-driven colorectal cancer identifies hallmarks of the human disease Disease Models & Mechanisms KRAS BRAF MAPK Colorectal cancer GEMM Genomic signatures |
| title | Cross-species analysis of genetically engineered mouse models of MAPK-driven colorectal cancer identifies hallmarks of the human disease |
| title_full | Cross-species analysis of genetically engineered mouse models of MAPK-driven colorectal cancer identifies hallmarks of the human disease |
| title_fullStr | Cross-species analysis of genetically engineered mouse models of MAPK-driven colorectal cancer identifies hallmarks of the human disease |
| title_full_unstemmed | Cross-species analysis of genetically engineered mouse models of MAPK-driven colorectal cancer identifies hallmarks of the human disease |
| title_short | Cross-species analysis of genetically engineered mouse models of MAPK-driven colorectal cancer identifies hallmarks of the human disease |
| title_sort | cross species analysis of genetically engineered mouse models of mapk driven colorectal cancer identifies hallmarks of the human disease |
| topic | KRAS BRAF MAPK Colorectal cancer GEMM Genomic signatures |
| url | http://dmm.biologists.org/content/7/6/613 |
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