Differential Effects of Trp53 Alterations in Murine Colorectal Cancer
Colorectal cancer (CRC) development is a multi-step process resulting in the accumulation of genetic alterations. Despite its high incidence, there are currently no mouse models that accurately recapitulate this process and mimic sporadic CRC. We aimed to develop and characterize a genetically engin...
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| Veröffentlicht in: | Cancers 2021-02, Vol.13 (4), p.808 |
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| creator | Betzler, Alexander M Nanduri, Lahiri K Hissa, Barbara Blickensdörfer, Linda Muders, Michael H Roy, Janine Jesinghaus, Moritz Steiger, Katja Weichert, Wilko Kloor, Matthias Klink, Barbara Schroeder, Michael Mazzone, Massimiliano Weitz, Jürgen Reissfelder, Christoph Rahbari, Nuh N Schölch, Sebastian |
| description | Colorectal cancer (CRC) development is a multi-step process resulting in the accumulation of genetic alterations. Despite its high incidence, there are currently no mouse models that accurately recapitulate this process and mimic sporadic CRC. We aimed to develop and characterize a genetically engineered mouse model (GEMM) of Apc/Kras/Trp53 mutant CRC, the most frequent genetic subtype of CRC.
Tumors were induced in mice with conditional mutations or knockouts in Apc, Kras, and Trp53 by a segmental adeno-cre viral infection, monitored via colonoscopy and characterized on multiple levels via immunohistochemistry and next-generation sequencing.
The model accurately recapitulates human colorectal carcinogenesis clinically, histologically and genetically. The Trp53 R172H hotspot mutation leads to significantly increased metastatic capacity. The effects of Trp53 alterations, as well as the response to treatment of this model, are similar to human CRC. Exome sequencing revealed spontaneous protein-modifying alterations in multiple CRC-related genes and oncogenic pathways, resulting in a genetic landscape resembling human CRC.
This model realistically mimics human CRC in many aspects, allows new insights into the role of TP53 in CRC, enables highly predictive preclinical studies and demonstrates the value of GEMMs in current translational cancer research and drug development. |
| doi_str_mv | 10.3390/cancers13040808 |
| format | Article |
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Tumors were induced in mice with conditional mutations or knockouts in Apc, Kras, and Trp53 by a segmental adeno-cre viral infection, monitored via colonoscopy and characterized on multiple levels via immunohistochemistry and next-generation sequencing.
The model accurately recapitulates human colorectal carcinogenesis clinically, histologically and genetically. The Trp53 R172H hotspot mutation leads to significantly increased metastatic capacity. The effects of Trp53 alterations, as well as the response to treatment of this model, are similar to human CRC. Exome sequencing revealed spontaneous protein-modifying alterations in multiple CRC-related genes and oncogenic pathways, resulting in a genetic landscape resembling human CRC.
This model realistically mimics human CRC in many aspects, allows new insights into the role of TP53 in CRC, enables highly predictive preclinical studies and demonstrates the value of GEMMs in current translational cancer research and drug development.</description><identifier>ISSN: 2072-6694</identifier><identifier>EISSN: 2072-6694</identifier><identifier>DOI: 10.3390/cancers13040808</identifier><identifier>PMID: 33671932</identifier><language>eng</language><publisher>Switzerland: MDPI AG</publisher><subject>Adenomatous polyposis coli ; Animal models ; Cancer ; Carcinogenesis ; Cell adhesion & migration ; Colonoscopy ; Colorectal cancer ; Colorectal carcinoma ; Drug development ; Experiments ; Genetic engineering ; Histology ; Immunohistochemistry ; Infections ; Laboratories ; Metastases ; Metastasis ; Mutation ; Mutation hot spots ; Next-generation sequencing ; p53 Protein ; Survival analysis ; Tumors</subject><ispartof>Cancers, 2021-02, Vol.13 (4), p.808</ispartof><rights>2021. This work is licensed under http://creativecommons.org/licenses/by/3.0/ (the “License”). Notwithstanding the ProQuest Terms and Conditions, you may use this content in accordance with the terms of the License.</rights><rights>2021 by the authors. 2021</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c421t-5d1b86abff58e9059aa1235ad3e168527520797ef1277debe435e218a379052f3</citedby><cites>FETCH-LOGICAL-c421t-5d1b86abff58e9059aa1235ad3e168527520797ef1277debe435e218a379052f3</cites><orcidid>0000-0002-7269-5433 ; 0000-0003-0012-3177 ; 0000-0003-4591-1046 ; 0000-0002-0258-6055</orcidid></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC7919037/pdf/$$EPDF$$P50$$Gpubmedcentral$$Hfree_for_read</linktopdf><linktohtml>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC7919037/$$EHTML$$P50$$Gpubmedcentral$$Hfree_for_read</linktohtml><link.rule.ids>230,314,727,780,784,885,27924,27925,53791,53793</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/33671932$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Betzler, Alexander M</creatorcontrib><creatorcontrib>Nanduri, Lahiri K</creatorcontrib><creatorcontrib>Hissa, Barbara</creatorcontrib><creatorcontrib>Blickensdörfer, Linda</creatorcontrib><creatorcontrib>Muders, Michael H</creatorcontrib><creatorcontrib>Roy, Janine</creatorcontrib><creatorcontrib>Jesinghaus, Moritz</creatorcontrib><creatorcontrib>Steiger, Katja</creatorcontrib><creatorcontrib>Weichert, Wilko</creatorcontrib><creatorcontrib>Kloor, Matthias</creatorcontrib><creatorcontrib>Klink, Barbara</creatorcontrib><creatorcontrib>Schroeder, Michael</creatorcontrib><creatorcontrib>Mazzone, Massimiliano</creatorcontrib><creatorcontrib>Weitz, Jürgen</creatorcontrib><creatorcontrib>Reissfelder, Christoph</creatorcontrib><creatorcontrib>Rahbari, Nuh N</creatorcontrib><creatorcontrib>Schölch, Sebastian</creatorcontrib><title>Differential Effects of Trp53 Alterations in Murine Colorectal Cancer</title><title>Cancers</title><addtitle>Cancers (Basel)</addtitle><description>Colorectal cancer (CRC) development is a multi-step process resulting in the accumulation of genetic alterations. Despite its high incidence, there are currently no mouse models that accurately recapitulate this process and mimic sporadic CRC. We aimed to develop and characterize a genetically engineered mouse model (GEMM) of Apc/Kras/Trp53 mutant CRC, the most frequent genetic subtype of CRC.
Tumors were induced in mice with conditional mutations or knockouts in Apc, Kras, and Trp53 by a segmental adeno-cre viral infection, monitored via colonoscopy and characterized on multiple levels via immunohistochemistry and next-generation sequencing.
The model accurately recapitulates human colorectal carcinogenesis clinically, histologically and genetically. The Trp53 R172H hotspot mutation leads to significantly increased metastatic capacity. The effects of Trp53 alterations, as well as the response to treatment of this model, are similar to human CRC. Exome sequencing revealed spontaneous protein-modifying alterations in multiple CRC-related genes and oncogenic pathways, resulting in a genetic landscape resembling human CRC.
This model realistically mimics human CRC in many aspects, allows new insights into the role of TP53 in CRC, enables highly predictive preclinical studies and demonstrates the value of GEMMs in current translational cancer research and drug development.</description><subject>Adenomatous polyposis coli</subject><subject>Animal models</subject><subject>Cancer</subject><subject>Carcinogenesis</subject><subject>Cell adhesion & migration</subject><subject>Colonoscopy</subject><subject>Colorectal cancer</subject><subject>Colorectal carcinoma</subject><subject>Drug development</subject><subject>Experiments</subject><subject>Genetic engineering</subject><subject>Histology</subject><subject>Immunohistochemistry</subject><subject>Infections</subject><subject>Laboratories</subject><subject>Metastases</subject><subject>Metastasis</subject><subject>Mutation</subject><subject>Mutation hot spots</subject><subject>Next-generation sequencing</subject><subject>p53 Protein</subject><subject>Survival 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(Basel)</addtitle><date>2021-02-15</date><risdate>2021</risdate><volume>13</volume><issue>4</issue><spage>808</spage><pages>808-</pages><issn>2072-6694</issn><eissn>2072-6694</eissn><abstract>Colorectal cancer (CRC) development is a multi-step process resulting in the accumulation of genetic alterations. Despite its high incidence, there are currently no mouse models that accurately recapitulate this process and mimic sporadic CRC. We aimed to develop and characterize a genetically engineered mouse model (GEMM) of Apc/Kras/Trp53 mutant CRC, the most frequent genetic subtype of CRC.
Tumors were induced in mice with conditional mutations or knockouts in Apc, Kras, and Trp53 by a segmental adeno-cre viral infection, monitored via colonoscopy and characterized on multiple levels via immunohistochemistry and next-generation sequencing.
The model accurately recapitulates human colorectal carcinogenesis clinically, histologically and genetically. The Trp53 R172H hotspot mutation leads to significantly increased metastatic capacity. The effects of Trp53 alterations, as well as the response to treatment of this model, are similar to human CRC. Exome sequencing revealed spontaneous protein-modifying alterations in multiple CRC-related genes and oncogenic pathways, resulting in a genetic landscape resembling human CRC.
This model realistically mimics human CRC in many aspects, allows new insights into the role of TP53 in CRC, enables highly predictive preclinical studies and demonstrates the value of GEMMs in current translational cancer research and drug development.</abstract><cop>Switzerland</cop><pub>MDPI AG</pub><pmid>33671932</pmid><doi>10.3390/cancers13040808</doi><orcidid>https://orcid.org/0000-0002-7269-5433</orcidid><orcidid>https://orcid.org/0000-0003-0012-3177</orcidid><orcidid>https://orcid.org/0000-0003-4591-1046</orcidid><orcidid>https://orcid.org/0000-0002-0258-6055</orcidid><oa>free_for_read</oa></addata></record> |
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| source | Elektronische Zeitschriftenbibliothek - Frei zugängliche E-Journals; PubMed Central Open Access; MDPI - Multidisciplinary Digital Publishing Institute; PubMed Central |
| subjects | Adenomatous polyposis coli Animal models Cancer Carcinogenesis Cell adhesion & migration Colonoscopy Colorectal cancer Colorectal carcinoma Drug development Experiments Genetic engineering Histology Immunohistochemistry Infections Laboratories Metastases Metastasis Mutation Mutation hot spots Next-generation sequencing p53 Protein Survival analysis Tumors |
| title | Differential Effects of Trp53 Alterations in Murine Colorectal Cancer |
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