DAPK1 loss triggers tumor invasion in colorectal tumor cells

Cell Death Dis. 2019 Nov 26;10(12):895. doi: 10.1038/s41419-019-2122-z.


Colorectal cancer (CRC) is one of the leading cancer-related causes of death worldwide. Despite the improvement of surgical and chemotherapeutic treatments, as of yet, the disease has not been overcome due to metastasis to distant organs. Hence, it is of great relevance to understand the mechanisms responsible for metastasis initiation and progression and to identify novel metastatic markers for a higher chance of preventing the metastatic disease. The Death-associated protein kinase 1 (DAPK1), recently, has been shown to be a potential candidate for regulating metastasis in CRC. Hence, the aim of the study was to investigate the impact of DAPK1 protein on CRC aggressiveness. Using CRISPR/Cas9 technology, we generated DAPK1-deficient HCT116 monoclonal cell lines and characterized their knockout phenotype in vitro and in vivo. We show that loss of DAPK1 implemented changes in growth pattern and enhanced tumor budding in vivo in the chorioallantoic membrane (CAM) model. Further, we observed more tumor cell dissemination into chicken embryo organs and increased invasion capacity using rat brain 3D in vitro model. The novel identified DAPK1-loss gene expression signature showed a stroma typical pattern and was associated with a gained ability for remodeling the extracellular matrix. Finally, we suggest the DAPK1-ERK1 signaling axis being involved in metastatic progression of CRC. Our results highlight DAPK1 as an anti-metastatic player in CRC and suggest DAPK1 as a potential predictive biomarker for this cancer type.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Antigens, Neoplasm / metabolism
  • CRISPR-Cas Systems / genetics
  • Cell Adhesion Molecules / metabolism
  • Cell Proliferation
  • Chick Embryo
  • Chorioallantoic Membrane / metabolism
  • Clone Cells
  • Colorectal Neoplasms / enzymology*
  • Colorectal Neoplasms / genetics
  • Colorectal Neoplasms / pathology*
  • Death-Associated Protein Kinases / deficiency*
  • Death-Associated Protein Kinases / metabolism
  • Extracellular Matrix / metabolism
  • Gene Expression Regulation, Neoplastic
  • Gene Knockout Techniques
  • HCT116 Cells
  • Humans
  • MAP Kinase Signaling System
  • Neoplasm Invasiveness
  • Neoplasm Metastasis
  • Rats, Wistar
  • Reproducibility of Results
  • Spheroids, Cellular / metabolism
  • Spheroids, Cellular / pathology
  • Tumor Burden


  • Antigens, Neoplasm
  • Cell Adhesion Molecules
  • TACSTD2 protein, human
  • DAPK1 protein, human
  • Death-Associated Protein Kinases