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bioRxiv · 10.1101/760934

CD99 regulates cancer cell transendothelial migration and endothelial cell function via CDC42 and actin remodelling

Mannion, A. J.·Odell, A. F.·Taylor, A.·Jones, P. F.·Cook, G. P.
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Abstract

Metastasis requires tumour cells to cross endothelial cell (EC) barriers and this occurs using mechanisms similar to those used by extravasating leucocytes during inflammation. The cell surface receptor CD99 is expressed by leucocytes and EC and participates in inflammatory transendothelial migration (TEM). CD99 is also expressed by tumour cells and we have analysed its role in tumour progression and cancer cell TEM. In a xenograft model, CD99 expression inhibited the metastatic progression of human breast cancer. In vitro, tumour cell CD99 was required for adhesion to ECs. However, tumour cell CD99 inhibited the invasion of the endothelial barrier by breast and prostate cancer cells and TEM itself. Furthermore, tumour cell CD99 depletion was associated with cytoskeletal remodelling. Loss of EC CD99 enhanced endothelial barrier function and reduced tumour cell TEM. Mechanistically, CD99 loss enhanced the expression and activity of CDC42, a known cytoskeletal organiser. CDC42 positively regulates EC angiogenic activity and the enhanced CDC42 activity resulting from loss of EC CD99 increased angiogenesis. As a signal transduction hub, CDC42 activity impacts upon many of the hallmarks of cancer. The functional link between CD99 and CDC42 identified here implicates CD99 in regulating these diverse pathways by modulation of CDC42 activity.

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Mannion, A. J., Odell, A. F., Taylor, A., Jones, P. F., Cook, G. P.. 2019-09-08. CD99 regulates cancer cell transendothelial migration and endothelial cell function via CDC42 and actin remodelling. https://doi.org/10.1101/760934

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