Developers
Kerstin Keysselt, Karen Rother, Joerg Galle, Gabriela Aust, etc.
Description of the technology
Mutations in mismatch repair (MMR) genes result in microsatellite instability (MSI) and early onset of colorectal cancer, including its development in process of ageing. This technology was created for study of formation of Lynch syndrome/hereditary nonpolyposis colorectal cancer. It originates in heterozygous germline mutations in mismatch repair (MMR) genes. Among them, mutations of MutS homolog 2 (MSH2) and MutL homolog 1 (MLH1) are the most common.
In order to develop this technology the culture cell model of intestinal epithelium was used. Intestinal epithelium is maintained by intestinal stem cells (ISCs). The identification of signaling pathways responsible for their
The time scale, sequence and extension of molecular and phenotypic changes in the epithelium preceding the onset of intestinal tumors were examined. To analyze and understand the profile of intestinal stem cell (ISC) transformations, MSI and growth characteristics of organoids were quantified in
In summary, as highlighted by organoid model, molecular alterations continuously proceeded long before tumor onset in
Practical application
The technology, using intestinal organoids of mice with MMR deficiency and those of control mice, enables the study and understanding the accumulation of genetic imbalances during ageing,
This study allows to develop early interventions that suppress essential steps in
Laboratories
- Department of Surgery, Research Laboratories, University of Leipzig, Leipzig (Germany)
- Interdisciplinary Center for Bioinformatics (IZBI), University of Leipzig, Leipzig (Germany)
- Interdisciplinary Center for Clinical Research Leipzig (IZKF),
Core-Unit DNA Technologies, University of Leipzig, Leipzig (Germany) - Institute for Medical Statistics, Informatics and Epidemiology, University of Leipzig, Leipzig (Germany)
Links
http://www.nature.com/onc/journal/vaop/ncurrent/full/onc2016429a.htmlPublications
- Keysselt, K. et al. «Different in vivo and in vitro transformation of intestinal stem cells in mismatch repair deficiency." Oncogene, 2016 Dec 12. doi:10.1038/onc.2016.429. (Advance online publication).
- Hamidouche, Z. et al. «Bistable Epigenetic States Explain
Age-Dependent Decline in Mesenchymal Stem Cell Heterogeneity." Stem Cells. 2016 Oct 13. doi: 10.1002/stem.2514 - Thalheim, T. et al. «Stem cell competition in the gut: insights from
multi-scale computational modelling." 13.121 J R Soc Interface. (2016): 20160218.