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Oncogene. 2019 May;38(19):3598-3615. doi: 10.1038/s41388-018-0667-4. Epub 2019 Jan 16.

Invadopodia are chemosensing protrusions that guide cancer cell extravasation to promote brain tropism in metastasis.

Author information

1
Department of Surgery, Division of Urology, Schulich School of Medicine and Dentistry, Western University, London, ON, Canada. karla.williams@ubc.ca.
2
Translational Prostate Cancer Research Laboratory, Lawson Health Research Institute, London, ON, Canada. karla.williams@ubc.ca.
3
Translational Breast Cancer Research Unit, Lawson Health Research Institute, London, ON, Canada. karla.williams@ubc.ca.
4
Faculty of Pharmaceutical Sciences, University of British Columbia, Vancouver, BC, Canada. karla.williams@ubc.ca.
5
Department of Surgery, Division of Urology, Schulich School of Medicine and Dentistry, Western University, London, ON, Canada.
6
Translational Prostate Cancer Research Laboratory, Lawson Health Research Institute, London, ON, Canada.
7
Department of Urology, Mayo Clinic, Rochester, MN, USA.
8
Faculty of Pharmaceutical Sciences, University of British Columbia, Vancouver, BC, Canada.
9
Department of Medical Biophysics, Schulich School of Medicine and Dentistry, Western University, London, ON, Canada.
10
Robarts Research Institute, Western University, London, ON, Canada.
11
Translational Breast Cancer Research Unit, Lawson Health Research Institute, London, ON, Canada.
12
Departments of Oncology, and Pathology and Laboratory Medicine, Schulich School of Medicine and Dentistry, Western University, London, ON, Canada.
13
Department of Surgery, Division of Urology, Schulich School of Medicine and Dentistry, Western University, London, ON, Canada. leong.hon@mayo.edu.
14
Translational Prostate Cancer Research Laboratory, Lawson Health Research Institute, London, ON, Canada. leong.hon@mayo.edu.
15
Department of Urology, Mayo Clinic, Rochester, MN, USA. leong.hon@mayo.edu.

Abstract

Invadopodia are cell protrusions that mediate cancer cell extravasation but the microenvironmental cues and signaling factors that induce invadopodia formation during extravasation remain unclear. Using intravital imaging and loss of function experiments, we determined invadopodia contain receptors involved in chemotaxis, namely GABA receptor and EGFR. These chemotaxis capabilities are mediated in part by PAK1 which controls invadopodia responsiveness to ligands such as GABA and EGF via assembly, stability, and turnover of invadopodia in vivo. PAK1 knockdown rendered cells unresponsive to chemotactic stimuli present in the stroma, resulting in dramatically lower rates of cancer cell extravasation and metastatic colony formation compared to stimulated cancer cells. In an experimental mouse model of brain metastasis, inhibition of PAK1 significantly reduced overall tumor burden and reduced the average size of brain metastases. In summary, invadopodia contain chemotaxis receptors that can respond to microenvironmental cues to guide cancer cell extravasation, and when PAK1 is depleted, brain tropism of metastatic breast cancer cells is significantly reduced, blocking secondary colony growth at sites otherwise permissive for metastatic outgrowth.

PMID:
30651600
PMCID:
PMC6756237
DOI:
10.1038/s41388-018-0667-4
[Indexed for MEDLINE]
Free PMC Article

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