Loss of tumor-derived SMAD4 enhances primary tumor growth but not metastasis following BMP4 signalling

We have reported previously that in preclinical models, BMP4 is a potent inhibitor of breast cancer metastasis and that high BMP4 protein levels predict favourable patient outcome. Here, we investigated the requirement for functional SMAD4 in mediating the anti-metastatic response of BMP4, given reports of promotion of metastasis by BMP4 in cancers where SMAD4 is frequently deleted. BMP4-induced inhibition of metastasis does not require functional SMAD4 in tumor cells. However, tumor cell intrinsic signalling using a constitutively active BMP receptor does require functional SMAD4 to suppress metastasis, thus implicating BMP4 mediated paracrine signalling as a contributor to the inhibition of metastasis.