Neuropilin-2 upregulation by stromal TGFβ1 induces lung disseminated tumour cells dormancy escape and promotes metastasis outgrowth

Abstract Metastasis is the main cause of death from solid tumours and, therefore, identifying the mechanisms that govern metastatic growth poses a major biomedical challenge. We and others have contributed to demonstrate that tumour microenvironment (TME) signals regulate the fate and survival of disseminated tumour cells (DTCs) in secondary organs. However, very little is known about the role of the nervous system mediators in this process. We have previously described that neuropilin-2 (NRP2) expression in breast cancer correlates with bad prognosis. Here we describe that NRP2 positively regulates breast and head and neck cancer cells proliferation, invasion and survival in vitro. NRP2 deletion in tumour cells inhibits tumour growth in vivo and decreases the number and size of lung metastases by promoting p27-mediated lung DTCs quiescence. Moreover, we show that several abundant stromal cells of the lung, such as fibroblasts and macrophages, induce NRP2 upregulation in DTCs, through secretion of TGFβ1. Therefore, we conclude that the TGFβ1-NRP2 axis is a new key dormancy awakening inducer, promoting DTCs proliferation and lung metastases development, positioning NRP2 expression as a central biomarker to predict metastatic recurrences and as a potential candidate for advanced therapies.