title: DAPK loss in colon cancer tumor buds: implications for migration capacity of disseminating tumor cells.
abstract: 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.
authors.affiliation: Experimental Tumor Pathology, Institute of Pathology, Friedrich-Alexander University of Erlangen-Nürnberg (FAU), Erlangen, Germany.
authors.forename: Jelena
authors.initials: J
authors.lastname: Ivanovska
authors.affiliation: Institute of Pathology, University of Bern, Bern, Switzerland.
authors.forename: Inti
authors.initials: I
authors.lastname: Zlobec
authors.affiliation: Experimental Tumor Pathology, Institute of Pathology, Friedrich-Alexander University of Erlangen-Nürnberg (FAU), Erlangen, Germany.
authors.forename: Stefan
authors.initials: S
authors.lastname: Forster
authors.affiliation: Institute of Pathology, University of Bern, Bern, Switzerland.
authors.forename: Eva
authors.initials: E
authors.lastname: Karamitopoulou
authors.affiliation: Institute of Pathology, University of Bern, Bern, Switzerland.
authors.forename: Heather
authors.initials: H
authors.lastname: Dawson
authors.affiliation: Institute of Pathology, University of Bern, Bern, Switzerland.
authors.forename: Viktor Hendrik
authors.initials: VH
authors.lastname: Koelzer
authors.affiliation: Institute of Pathology, Friedrich-Alexander University of Erlangen-Nürnberg (FAU), Erlangen, Germany.
authors.forename: Abbas
authors.initials: A
authors.lastname: Agaimy
authors.affiliation: Department of Anatomy, Friedrich-Alexander University of Erlangen-Nürnberg (FAU), Erlangen, Germany.
authors.forename: Fabian
authors.initials: F
authors.lastname: Garreis
authors.affiliation: Institute of Pathology, Friedrich-Alexander University of Erlangen-Nürnberg (FAU), Erlangen, Germany.
authors.forename: Stephan
authors.initials: S
authors.lastname: Söder
authors.affiliation: Experimental Tumor Pathology, Institute of Pathology, Friedrich-Alexander University of Erlangen-Nürnberg (FAU), Erlangen, Germany.
authors.forename: William
authors.initials: W
authors.lastname: Laqua
authors.affiliation: Institute of Pathology, University of Bern, Bern, Switzerland.
authors.forename: Alessandro
authors.initials: A
authors.lastname: Lugli
authors.affiliation: Institute of Pathology, Friedrich-Alexander University of Erlangen-Nürnberg (FAU), Erlangen, Germany.
authors.forename: Arndt
authors.initials: A
authors.lastname: Hartmann
authors.affiliation: Institute of Pathology, Friedrich-Alexander University of Erlangen-Nürnberg (FAU), Erlangen, Germany.|Institute of Pathology, University of Bern, Bern, Switzerland.
authors.forename: Tilman T
authors.initials: TT
authors.lastname: Rau
authors.affiliation: Experimental Tumor Pathology, Institute of Pathology, Friedrich-Alexander University of Erlangen-Nürnberg (FAU), Erlangen, Germany.|Institute of Pathology, Friedrich-Alexander University of Erlangen-Nürnberg (FAU), Erlangen, Germany.
authors.forename: Regine
authors.initials: R
authors.lastname: Schneider-Stock
mesh_terms: D000368:Aged; D018938:Caco-2 Cells; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000502:physiology*; D015331:Cohort Studies; D003110:Colonic Neoplasms / Q000201:enzymology* / Q000473:pathology*; D064550:Death-Associated Protein Kinases / Q000172:deficiency* / Q000378:metabolism; D005260:Female; D045325:HCT116 Cells; D006801:Humans; D007150:Immunohistochemistry; D008297:Male; D012189:Retrospective Studies; D014162:Transfection
chemical_list: D064550:Death-Associated Protein Kinases
keywords: DAPK; colorectal cancer; migration; tumour budding