Oncotarget

Research Papers:

Drosophila homologue of Diaphanous 1 (DIAPH1) controls the metastatic potential of colon cancer cells by regulating microtubule-dependent adhesion

Yuan-Na Lin _, Ridhirama Bhuwania, Kira Gromova, Antonio Virgilio Failla, Tobias Lange, Kristoffer Riecken, Stefan Linder, Matthias Kneussel, Jakob R. Izbicki and Sabine Windhorst

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Oncotarget. 2015; 6:18577-18589. https://doi.org/10.18632/oncotarget.4094

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Abstract

Yuan-Na Lin1,2, Ridhirama Bhuwania3, Kira Gromova4, Antonio Virgilio Failla5, Tobias Lange6, Kristoffer Riecken7, Stefan Linder3, Matthias Kneussel4, Jakob R. Izbicki1, Sabine Windhorst2

1Department of General, Visceral and Thoracic Surgery, University Medical Center Hamburg-Eppendorf, Hamburg, Germany

2Department of Biochemistry and Signal Transduction, University Medical Center Hamburg-Eppendorf, Hamburg, Germany

3Institute for Microbiology, Virology and Hygiene, University Medical Center Hamburg-Eppendorf, Hamburg, Germany

4Department of Molecular Neurogenetics, Center for Molecular Neurobiology, ZMNH, University Medical Center Hamburg-Eppendorf, Hamburg, Germany

5Microscopy Imaging Facility, University Medical Center Hamburg-Eppendorf, Hamburg, Germany

6Department of Anatomy and Experimental Morphology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany

7Department of Stem Cell Transplantation, University Medical Center Hamburg-Eppendorf, Hamburg, Germany

Correspondence to:

Sabine Windhorst, e-mail: s.windhorst@uke.uni-hamburg.de

Keywords: colon cancer, cytoskeleton, formins, cellular adhesion, metastasis

Received: April 14, 2015     Accepted: May 11, 2015     Published: May 25, 2015

ABSTRACT

Drosophila homologue of Diaphanous 1 (DIAPH1) regulates actin polymerization and microtubule (MT) stabilization upon stimulation with lysophosphatidic acid (LPA). Recently, we showed strongly reduced lung metastasis of DIAPH1-depleted colon cancer cells but we found accumulations of DIAPH1-depleted cells in bone marrow. Here, we analyzed possible organ- or tissue-specific metastasis of DIAPH1-depleted HCT-116 cells. Our data confirmed that depletion of DIAPH1 strongly inhibited lung metastasis and revealed that, in contrast to control cells, DIAPH1-depleted cells did not form metastases in further organs. Detailed mechanistic analysis on cells that were not stimulated with LPA to activate the cytoskeleton-modulating activity of DIAPH1, revealed that even under basal conditions DIAPH1 was essential for cellular adhesion to collagen. In non-stimulated cells DIAPH1 did not control actin dynamics but, interestingly, was essential for stabilization of microtubules (MTs). Additionally, DIAPH1 controlled directed vesicle trafficking and with this, local clustering of the adhesion protein integrin-β1 at the plasma membrane. Therefore, we conclude that under non-stimulating conditions DIAPH1 controls cellular adhesion by stabilizing MTs required for local clustering of integrin-β1 at the plasma membrane. Thus, blockade of DIAPH1-tubulin interaction may be a promising approach to inhibit one of the earliest steps in the metastatic cascade of colon cancer.


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