SP 3

Molecular analysis of stem cell-associated genes in colorectal cancer (CRC)

The metastasis of colorectal cancer (CRC) cells from the initial tumor to distant organs is a major problem in CRC patient survival, and a major organ of CRC metastasis is the liver.  Previous studies in this laboratory, and by others, showed that major genomic changes occur in colorectal cancer, and that the resulting metastases also exhibited these genomic changes. Furthermore, preliminary gene expression analysis of CRC tumors and their metastases resulted in the identification of genes, as well as molecular pathways, which might play a role in CRC proliferation, invasion and metastasis, and a subset of these genes were found in the respective regions of genomic change (Stange et al. Gut 59, 1236-1244, 2010).  

The most significant candidate genes/gene products found during this initial CRC tumor genome/ expression screening appear to be stem cell associated and are currently being analysed, in vitro, by transient/ stable over expression or shRNA induced inhibition in established CRC cell lines. Proliferation, adhesion and migration assays are used to identify phenotypes, in vitro, and microarray analysis is being performed in order to find further interaction partners. Several further analyses such as chromosomal immunoprecipitation (ChIP), protein-protein binding studies and global DNA methylation are also being initiated for specific candidates. Furthermore, the modified cell lines developed in this study will be used in a mouse metastasis model as a tool to analyse changes in the metastatic potential of these cells.

In a separate study, genes involved in CRC tumor formation and metastasis are being introduced into primary mouse intestine/ adenoma cells cultivated in a 3D in vitro organotypic culture system. Molecular biological analysis of these cells should allow further insights into the mechanisms responsible for CRC tumor formation and metastasis.

Team SP3

PD Dr. rer. nat. M. Rogers, Prof. Dr. rer. nat. P. Lichter, Dr. rer. nat. B. Radlwimmer, V. Kalter

Project-related key publications

Ernst A, Aigner M, Nakata S, Engel F, Schlotter M, Kloor M, Brand K, Schmitt S, Steinert G, Rahbari N, Koch M, Radlwimmer B, Weitz J, Lichter P (2011). A gene signature distinguishing CD133(hi) from CD133(-) colorectal cancer cells: essential role for EGR1 and downstream factors. Pathology 2011 43(3): 220-227.

Stange DE, Engel F, Longerich T, Koo BK, Koch M, Delhomme N, Aigner M, Toedt G, Schirmacher P, Lichter P, Weitz J, Radlwimmer B. Expression of an ASCL2 related stem cell signature and IGF2 in colorectal cancer liver metastases with 11p15.5 gain. Gut. 2010 Sep;59(9):1236-44. Epub 2010 May 17.

Pfister S, Janzarik WG, Remke M, Ernst A, Werft W, Becker N, Toedt G, Wittmann A, Kratz C, Olbrich H, Ahmadi R, Thieme B, Joos S, Radlwimmer B, Kulozik A, Pietsch T, Herold-Mende C, Gnekow A, Reifenberger G, Korshunov A, Scheurlen W, Omran H, Lichter P. BRAF gene duplication constitutes a novel mechanism of MAPK pathway activation in low-grade astrocytomas. J Clin Invest 2008;118:1739-49. Published online 2008 April 8.

Schlaeger C, Longerich T, Schiller C, Bewerunge P, Mehrabi A, Eils R, Lichter P, Schirmacher P, Radlwimmer B. Etiology-dependent molecular mechanisms in human hepatocarcinogenesis. Hepatology 2008 Feb;47(2):511-20.

Sticht C, Freier K, Knöpfle K, Flechtenmacher C, Pungs S, Hofele C, Hahn M, Joos S, Lichter P. Activation of MAP kinase signaling through ERK5 but not ERK1 expression is associated with lymph node metastases in oral squamous cell carcinoma (OSCC). Neoplasia 2008;10:462-70.

Tews B, Roerig P, Hartmann C, Hahn M, Felsberg J, Blaschke B, Sabel M, Kunitz A, Toedt G, Neben K, Benner A, von Deimling A, Reifenberger G, Lichter P. Hypermethylation and transcriptional downregulation of the CITED4 gene at 1p34.2 in oligodendroglial tumors with allelic losses on 1p and 19q. Oncogene 2007 Jul 26;26(34):5010-6. Epub 2007 Feb 19.

Fensterer H, Radlwimmer B, Strater J, Buchholz M, Aust DE, Julie C, Radvanyi F, Nordlinger B,  Belluco C, van Cutsem E, Kohne CH, Kestler HA, Schwaenen C, Nessling M, Lutz MP, Lichter P, Gress TM. Matrix-comparative genomic hybridization from multicenter formalin-fixed paraffin-embedded colorectal cancer tissue blocks. BMC Cancer 2007;7:58.

Stange DE, Radlwimmer B, Schubert F, Traub F, Pich A, Lejeune A, Toedt G, Mendrzyk F, Lehmann U, Eils R, Kreipe H, Lichter P. High resolution genomic profiling reveals association of chromosomal aberrations on 1q and 16p with histological and genetic subgroups of invasive breast cancer. Clin Cancer Res 2006 Jan 15;12(2):345-52.

Mertens D, Wolf S, Tschuch C, Mund C, Kienle D, Ohl S, Schroeter P, Lyko F, Döhner H, Stilgenbauer S, Lichter P. Allelic silencing at the tumor-suppressor locus 13q14.3 suggests an epigenetic tumor-suppressor mechanism. Proc Natl Acad Sci USA 2006 May 16; 103(20): 7741–7746. Published online 2006 May 9.

Schwaenen C, Nessling M, Wessendorf S, Salvi T, Wrobel G, Radlwimmer B, Kestler HA, Haslinger C, Stilgenbauer S, Döhner H, Bentz M, Lichter P. Automated array-based genomic profiling in chronic lymphocytic leukemia: development of a clinical tool and discovery of recurrent genomic alterations. Proc Natl Acad Sci USA 2004 Jan 27;101(4):1039-44. Epub 2004 Jan 16.

Holzmann K, Kohlhammer H, Schwaenen C, Wessendorf S, Kessler HA, Schwoerer A, Rau B, Radlwimmer B, Döhner H, Lichter P, Gress T, Bentz M. Genomic DNA-chip hybridization reveals a higher incidence of genomic amplifications in pancreatic cancer than conventional comparative genomic hybridization and leads to the identification of novel candidate genes. Cancer Res 2004 Jul 1;64(13):4428-33.

Thuerigen O, Schneeweiss A, Toedt G, Warnat P, Hahn M, Kramer H, Brors B, Rudlowski C, Benner A, Schuetz F, Tews B, Eils R, Sinn HP, Sohn C, Lichter P. Gene expression signature predicting pathologic complete response with gemcitabine, epirubicin, and docetaxel in primary breast cancer. J Clin Oncol 2006 Apr 20;24(12):1839-45.

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