Dataset Information

Differential Effects of Trp53 Alterations in Murine Colorectal Cancer.

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.

SUBMITTER: Betzler AM

PROVIDER: S-EPMC7919037 | biostudies-literature | 2021 Feb

REPOSITORIES: biostudies-literature

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Differential Effects of Trp53 Alterations in Murine Colorectal Cancer.

Betzler Alexander M AM Nanduri Lahiri K LK Hissa Barbara B Blickensdörfer Linda L Muders Michael H MH Roy Janine J Jesinghaus Moritz M Steiger Katja K Weichert Wilko W Kloor Matthias M Klink Barbara B Schroeder Michael M Mazzone Massimiliano M Weitz Jürgen J Reissfelder Christoph C Rahbari Nuh N NN Schölch Sebastian S

Cancers 20210215 4

<h4>Background</h4>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.<h4>Methods</h4>Tumors were induced in mice with conditional mutations or knockouts i ...[more]

PMID: 33671932

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Project description:BACKGROUND:Heparan sulfate proteoglycans (HSPGs) are complex molecules which play a role in the invasion and growth and metastatic properties of cancerous cells. In this work we analyze changes in the patterns of expression of HSPGs in left sided colorectal cancer (LSCRC), both metastatic and non-metastatic, and the results are also compared with those previously obtained for right sided tumors (RSCRCs). METHODS:Eighteen LSCRCs were studied using qPCR to analyze the expression of both the proteoglycan core proteins and the enzymes involved in heparan sulfate chain biosynthesis. Certain HSPGs also carry chondroitin sulfate chains and so we also studied the genes involved in its biosynthesis. The expression of certain genes that showed significant expression differences were also analysed using immunohistochemical techniques. RESULTS:Changes in proteoglycan core proteins were dependent on their location, and the main differences between metastatic and non-metastatic tumors affected cell-surface glypicans, while other molecules were quite similar. Glypicans were also responsible for the main differences between RS- and LS- malignances. Regarding the biosynthesis of heparan sulfate chains, differential alterations in transcription depending on the presence or not of metastasis affected genes involved in the modification of uronic acid (epimerization and 2-O sulfation), and some isoforms responsible for sulfation of glucosamine (NDST1, HS6ST1). Moreover, in RSCRCs differences were preferentially found in the expression of genes involved in C6 and C3 sulfation of glucosamine, but not in NDSTs or SULFs. Finally, synthesis of chondroitin sulfate showed some alterations, which affected various steps, including polimerization and the modification of chains, but the main variations dependent on the presence of metastases were epimerization and 6C sulfation; however, when compared with RSCRCs, the essential divergences affected polymerization of the chains and the 6C sulfation of the galactosamine residue. CONCLUSIONS:We evidenced alterations in the expression of HSPGs, including the expression of cell surface core proteins, many glycosiltransferases and some enzymes that modify the GAG chains in LSCRCs, but this was dependent on the metastatic nature of the tumor. Some of these alterations are shared with RSCRCs, while others, focused on specific gene groups, are dependent on tumor localization.

Dataset Information

Differential Effects of Trp53 Alterations in Murine Colorectal Cancer.

Publications

Differential Effects of Trp53 Alterations in Murine Colorectal Cancer.

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