The Calcineurin-NFAT-Angiopoietin-2 Signaling Axis in Lung Endothelium Is Critical for the Establishment of Lung Metastases

The premetastatic niche is a predetermined site of metastases, awaiting the influx of tumor cells. However, the regulation of the angiogenic switch at these sites has not been examined. Here, we demonstrate that the calcineurin and nuclear factor of activated T cells (NFAT) pathway is activated specifically in lung endothelium prior to the detection of tumor cells that preferentially metastasize to the lung. Upregulation of the calcineurin pathway via deletion of its endogenous inhibitor Dscr1 leads to a significant increase in lung metastases due to increased expression of a newly identified NFAT target, Angiopoietin-2 (ANG2). Increased VEGF levels specifically in the lung, and not other organ microenvironments, trigger a threshold of calcineurin-NFAT signaling that transactivates Ang2 in lung endothelium. Further, we demonstrate that overexpression of DSCR1 or the ANG2 receptor, soluble TIE2, prevents the activation of lung endothelium, inhibiting lung metastases in our mouse models. Our studies provide insights into mechanisms underlying angiogenesis in the premetastatic niche and offer targets for lung metastases. [Display omitted] •Calcineurin-NFAT is activated in lung endothelium of the premetastatic niche•Calcineurin-NFAT signaling upregulates ANG2 promoting the angiogenic switch•Hyperactivation of calcineurin in Dscr1−/− mice leads to increased lung metastases•Inhibiting calcineurin or ANG2 blocks endothelial activation and lung metastases Angiogenesis regulation in early metastatic lesions is not well understood. Minami, Ryeom, and colleagues now show that the activation of calcineurin-NFAT specifically in lung endothelium with tumor cells that metastasize to the lung. Dysregulating this pathway by deleting the calcineurin inhibitor Dscr1 leads to increased lung metastases due to the upregulation of the NFAT target Angiopoietin-2 (ANG2). Furthermore, these studies reveal that the inhibition of calcineurin signaling or sequestering ANG2 is sufficient to block lung endothelium activation and prevent lung metastases.