This is the first in vivo demonstration that thrombin cleavage of OPN has a major pathophysiological role in cancer, and this indicates that, despite the presence of the other OPN functionalities in OPNR153A, including the RGD site for binding to integrins αvb1, αvb3, and αvb5, the vCD44-binding domain, and the heparin- and hydroxyapatite-binding sites, resistance to thrombin cleavage in OPNR153A alone renders it incapable of supporting B16 tumor growth and metastasis, to an equal extent as the total absence of OPN. Here, SPP1 is linked to cancer.