DAPK1 loss triggers tumor invasion in colorectal tumor cells

Sara Steinmann; Philipp Kunze; Chuanpit Hampel; Markus Eckstein; Jesper Bertram Bramsen; Julienne K. Muenzner; Birgitta Carlé; Benardina Ndreshkjana; Stephan Kemenes; Pierluigi Gasparini; Oliver Friedrich; Claus Andersen; Carol Geppert; Shengbao Wang; Ilker Eyupoglu; Tobias Bäuerle; Arndt Hartmann; Regine Schneider-Stock

doi:10.1038/s41419-019-2122-z

DAPK1 loss triggers tumor invasion in colorectal tumor cells

Sara Steinmann, Philipp Kunze, Chuanpit Hampel, Markus Eckstein, Jesper Bertram Bramsen, Julienne K. Muenzner, Birgitta Carlé, Benardina Ndreshkjana, Stephan Kemenes, Pierluigi Gasparini, Oliver Friedrich, Claus Andersen, Carol Geppert, Shengbao Wang, Ilker Eyupoglu, Tobias Bäuerle, Arndt Hartmann, Regine Schneider-Stock^*

^*Corresponding author for this work

Department of Clinical Medicine - Department of Molecular Medicine (MOMA)

Research output: Contribution to journal/Conference contribution in journal/Contribution to newspaper › Journal article › Research › peer-review

48 Citations (Scopus)

Abstract

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.

Original language	English
Article number	895
Journal	Cell Death and Disease
Volume	10
Issue	12
Number of pages	19
ISSN	2041-4889
DOIs	https://doi.org/10.1038/s41419-019-2122-z
Publication status	Published - 2019

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Steinmann, S., Kunze, P., Hampel, C., Eckstein, M., Bertram Bramsen, J., Muenzner, J. K., Carlé, B., Ndreshkjana, B., Kemenes, S., Gasparini, P., Friedrich, O., Andersen, C., Geppert, C., Wang, S., Eyupoglu, I., Bäuerle, T., Hartmann, A., & Schneider-Stock, R. (2019). DAPK1 loss triggers tumor invasion in colorectal tumor cells. Cell Death and Disease, 10(12), Article 895. https://doi.org/10.1038/s41419-019-2122-z

@article{a91df1d9bddf43d485cc86d7e9bccb0a,

title = "DAPK1 loss triggers tumor invasion in colorectal tumor cells",

abstract = "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.",

author = "Sara Steinmann and Philipp Kunze and Chuanpit Hampel and Markus Eckstein and {Bertram Bramsen}, Jesper and Muenzner, {Julienne K.} and Birgitta Carl{\'e} and Benardina Ndreshkjana and Stephan Kemenes and Pierluigi Gasparini and Oliver Friedrich and Claus Andersen and Carol Geppert and Shengbao Wang and Ilker Eyupoglu and Tobias B{\"a}uerle and Arndt Hartmann and Regine Schneider-Stock",

year = "2019",

doi = "10.1038/s41419-019-2122-z",

language = "English",

volume = "10",

journal = "Cell Death and Disease",

issn = "2041-4889",

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Steinmann, S, Kunze, P, Hampel, C, Eckstein, M, Bertram Bramsen, J, Muenzner, JK, Carlé, B, Ndreshkjana, B, Kemenes, S, Gasparini, P, Friedrich, O, Andersen, C, Geppert, C, Wang, S, Eyupoglu, I, Bäuerle, T, Hartmann, A & Schneider-Stock, R 2019, 'DAPK1 loss triggers tumor invasion in colorectal tumor cells', Cell Death and Disease, vol. 10, no. 12, 895. https://doi.org/10.1038/s41419-019-2122-z

TY - JOUR

T1 - DAPK1 loss triggers tumor invasion in colorectal tumor cells

AU - Steinmann, Sara

AU - Kunze, Philipp

AU - Hampel, Chuanpit

AU - Eckstein, Markus

AU - Bertram Bramsen, Jesper

AU - Muenzner, Julienne K.

AU - Carlé, Birgitta

AU - Ndreshkjana, Benardina

AU - Kemenes, Stephan

AU - Gasparini, Pierluigi

AU - Friedrich, Oliver

AU - Andersen, Claus

AU - Geppert, Carol

AU - Wang, Shengbao

AU - Eyupoglu, Ilker

AU - Bäuerle, Tobias

AU - Hartmann, Arndt

AU - Schneider-Stock, Regine

PY - 2019

Y1 - 2019

N2 - 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.

AB - 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.

UR - http://www.scopus.com/inward/record.url?scp=85075610096&partnerID=8YFLogxK

U2 - 10.1038/s41419-019-2122-z

DO - 10.1038/s41419-019-2122-z

M3 - Journal article

C2 - 31772156

AN - SCOPUS:85075610096

SN - 2041-4889

VL - 10

JO - Cell Death and Disease

JF - Cell Death and Disease

IS - 12

M1 - 895

ER -

DAPK1 loss triggers tumor invasion in colorectal tumor cells

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