Research Papers:

This article has been corrected. Correction in: Oncotarget. 2017; 8(11):18615-16.

DAPK loss in colon cancer tumor buds: implications for migration capacity of disseminating tumor cells

Jelena Ivanovska _, Inti Zlobec, Stefan Forster, Eva Karamitopoulou, Heather Dawson, Viktor Hendrik Koelzer, Abbas Agaimy, Fabian Garreis, Stephan Söder, William Laqua, Alessandro Lugli, Arndt Hartmann, Tilman T. Rau and Regine Schneider-Stock

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Oncotarget. 2015; 6:36774-36788. https://doi.org/10.18632/oncotarget.4908

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Jelena Ivanovska1,*, Inti Zlobec3,*, Stefan Forster1,*, Eva Karamitopoulou3, Heather Dawson3, Viktor Hendrik Koelzer3, Abbas Agaimy2, Fabian Garreis4, Stephan Söder2, William Laqua1, Alessandro Lugli3, Arndt Hartmann2, Tilman T. Rau2,3, Regine Schneider-Stock1,2

1Experimental Tumor Pathology, Institute of Pathology, Friedrich-Alexander University of Erlangen-Nürnberg (FAU), Erlangen, Germany

2Institute of Pathology, Friedrich-Alexander University of Erlangen-Nürnberg (FAU), Erlangen, Germany

3Institute of Pathology, University of Bern, Bern, Switzerland

4Department of Anatomy, Friedrich-Alexander University of Erlangen-Nürnberg (FAU), Erlangen, Germany

*These authors have contributed equally to this work

Correspondence to:

Regine Schneider-Stock, e-mail: [email protected]

Keywords: DAPK, colorectal cancer, tumour budding, migration

Received: May 27, 2015     Accepted: August 11, 2015     Published: August 21, 2015


Defining new therapeutic strategies to overcome therapy resistance due to tumor heterogeneity in colon cancer is challenging. One option is to explore the molecular profile of aggressive disseminating tumor cells. The cytoskeleton-associated Death-associated protein kinase (DAPK) is involved in the cross talk between tumor and immune cells at the invasion front of colorectal cancer. Here dedifferentiated tumor cells histologically defined as tumor budding are associated with a high risk of metastasis and poor prognosis. Analyzing samples from 144 colorectal cancer patients we investigated immunhistochemical DAPK expression in different tumor regions such as center, invasion front, and buds. Functional consequences for tumor aggressiveness were studied in a panel of colon tumor cell lines using different migration, wound healing, and invasion assays. DAPK levels were experimentally modified by siRNA transfection and overexpression as well as inhibitor treatments. We found that DAPK expression was reduced towards the invasion front and was nearly absent in tumor buds. Applying the ECIS system with HCT116 and HCT116 stable lentiviral DAPK knock down cells (HCTshDAPK) we identified an important role for DAPK in decreasing the migratory capacity whereas proliferation was not affected. Furthermore, the migration pattern differed with HCTshDAPK cells showing a cluster-like migration of tumor cell groups. DAPK inhibitor treatment revealed that the migration rate was independent of DAPK’s catalytic activity. Modulation of DAPK expression level in SW480 and DLD1 colorectal cancer cells significantly influenced wound closure rate. DAPK seems to be a major player that influences the migratory capability of disseminating tumor cells and possibly affects the dynamic interface between pro- and anti-survival factors at the invasion front of colorectal cancer. This interesting and new finding requires further evaluation.

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