Cancer

Endothelial stem cell

Apoptosis

In vitro

Immunology

Metastasis

Extravasation

Programmed cell death

Cancer research

Genetics

Biochemistry

Biology

Necroptosis

Cell biology

Cancer cell

Nature

Human and murine tumour cells induce programmed necrosis (necroptosis) of endothelial cells, which promotes tumour cell extravasation and metastasis. A critical step in the metastatic spread of cancer is the escape of a circulating tumour cell from the blood stream across the endothelial barrier. This report identifies a novel mechanism that facilitates tumour cell extravasation. Tumour cells expressing amyloid precursor protein are shown to induce endothelial programmed necrosis (necroptosis) via DR6 signalling. Inhibition of necroptosis regulators reduces metastatic colonization in mouse models, suggesting that this is a relevant step for the systemic dissemination of cancers. Metastasis is the leading cause of cancer-related death in humans. It is a complex multistep process during which individual tumour cells spread primarily through the circulatory system to colonize distant organs1,2,3. Once in the circulation, tumour cells remain vulnerable, and their metastatic potential largely depends on a rapid and efficient way to escape from the blood stream by passing the endothelial barrier4,5,6,7,8,9. Evidence has been provided that tumour cell extravasation resembles leukocyte transendothelial migration7,8,9. However, it remains unclear how tumour cells interact with endothelial cells during extravasation and how these processes are regulated on a molecular level. Here we show that human and murine tumour cells induce programmed necrosis (necroptosis) of endothelial cells, which promotes tumour cell extravasation and metastasis. Treatment of mice with the receptor-interacting serine/threonine-protein kinase 1 (RIPK1)-inhibitor necrostatin-1 or endothelial-cell-specific deletion of RIPK3 reduced tumour-cell-induced endothelial necroptosis, tumour cell extravasation and metastasis. In contrast, pharmacological caspase inhibition or endothelial-cell-specific loss of caspase-8 promoted these processes. We furthermore show in vitro and in vivo that tumour-cell-induced endothelial necroptosis leading to extravasation and metastasis requires amyloid precursor protein expressed by tumour cells and its receptor, death receptor 6 (DR6), on endothelial cells as the primary mediators of these effects. Our data identify a new mechanism underlying tumour cell extravasation and metastasis, and suggest endothelial DR6-mediated necroptotic signalling pathways as targets for anti-metastatic therapies.

Tumour-cell-induced endothelial cell necroptosis via death receptor 6 promotes metastasis