Tumor Endothelial Notch Signaling Drives Metastasis via VCAM1

Dysregulated Notch signaling frequently occurs in numerous cancers and plays a key role in tumor progression; however, although Notch signaling has been extensively evaluated in tumors, its roles in the tumor stroma are less clear. Expression of the Notch intracellular domain (NICD), the cleavage product of ligand-bound Notch receptor, in endothelial cells (EC) induced senescence and elevated expression of proinflammatory cytokines in vitro. Having found that NICD expression was elevated in tumor vasculature in both melanoma and melanoma metastases and correlated with worse patient survival, Wieland, Rodriguez-Vita, and colleagues sought to elucidate the role of tumor EC Notch signaling in metastasis. Notch signaling in ECs was induced by cocultures of ECs with tumor cells expressing the Notch ligands DLL4 and JAG1 in vitro, and NICD expression was induced in ECs by tumor-infiltrating myeloid cells in vivo. Further, NICD expression was elevated in lung ECs in mice subcutaneously implanted with murine lung or melanoma cells compared to non–tumor bearing mice two weeks post-implantation, suggesting that EC Notch signaling is activated in premetastatic niches. Induction of NICD overexpression in ECs resulted in reduced growth and vascularization of subcutaneous primary tumors, elevated levels of neutrophils in primary tumors, blood, and lungs, and increased numbers of circulating tumor cells and metastases. Expression of NICD in ECs resulted in senescence, increased transcription of inflammatory cytokines and expression of the leukocyte adhesion molecule VCAM1, and promoted EC–tumor cell interaction and tumor cell transmigration in vitro. Similarly, activated EC Notch signaling was associated with EC senescence in primary tumors and metastases in vivo and promoted tumor cell extravasation and lung colonization. Treatment with antibodies targeting VCAM1 or Notch receptors prevented NICD-mediated lung colonization; further, anti-VCAM1 also significantly reduced neutrophil infiltration. Together, these results describe the mechanism by which endothelial Notch signaling promotes tumor cell extravasation and identify a potential antimetastatic therapeutic approach.

Wieland E, Rodriguez-Vita J, Liebler SS, Mogler C, Moll I, Herberich SE, et al. Endothelial Notch1 activity facilitates metastasis. Cancer Cell 2017 Feb 23 [Epub ahead of print].