Our lab previously reported that metastases are generally characterized by a core program of gene expression that activates tissue remodeling/vascularization, alters ion homeostasis, induces the oxidative metabolism, and silences extracellular matrix interactions. This core program distinguishes metastases from their originating primary tumors and from their destination host tissues. Therefore, the gene products involved are potential targets for anti-metastasis drug treatment. We tested inhibitors against the other three components. Individually, the low-specificity VEGFR blocker pazopanib (in vivo combined with marimastat), the anti-oxidant dimethyl sulfoxide, and the ionic modulators bumetanide and tetrathiomolybdate inhibited soft agar colony formation by breast and pancreatic cancer cell lines. In combination, the effects of these drugs were additive or synergistic. In two mouse models of cancer, the combination treatment with these drugs, administered immediately or delayed, dramatically reduced the occurrence of disseminated foci. The combination of tissue remodeling inhibitors, suppressors of the oxidative metabolism, and ion homeostasis modulators has strong promise for the treatment of metastases by multiple cancers.Metastasizing cells display a unique metabolism, which is very different from the Warburg effect that arises in primary tumors. Over short time frames, oxidative phosphorylation and ATP generation are prominent. Over longer time frames, mitochondrial biogenesis becomes a pronounced feature and aids metastatic success. It has not been known whether or how these two phenomena are connected. Here, we report that autocrine Osteopontin does indeed stimulate an increase in mitochondrial size, with the splice variant -c being more effective than the full-length form -a. Osteopontin-c achieves this via its receptor CD44v, jointly with the upregulation and co-ligation of SLC7A11. The signaling proceeds through activation of the known mitochondrial biogenesis inducer PGC-1. Peroxide is an important intermediate in this cascade and acts upstream of PGC-1 and is likely produced as a consequence of SLC7A11 recruitment and activation. In vivo, the suppression of the biogenesis-inducing mechanisms leads to a reduction in disseminated tumor mass. This study confirms a functional connection between the short-term oxidative metabolism and the longer-term mitochondrial biogenesis in cancer metastasis – both are induced by Osteopontin. The results imply possible mechanisms for treating metastasis.Since the original description in 1996, the interaction between the cytokine osteopontin (OPN) and the homing receptor CD44 has been extensively studied in cancer. Alternative splicing and extensive posttranslational modifications by both binding partners, and s well as the possibility for lateral recruitment of additional membrane receptors or soluble co-ligands into a complex have left the exact molecular requirements for high-affinity OPN-CD44 binding unresolved. We now report that there is a moderate engagement between the unmodified molecules, which results in curved double-reciprocal plots for OPN titration, suggesting the existence of two binding sites or two binding conformations. Structural constraint of OPN, by immobilization or by addition of heparin, is required for its strong ligation of CD44. This conformational adjustment may be essential for efficient CD44 interaction. The integrin aVß3 reflects additive binding, suggesting that the CD44 contact sites on OPN are downstream of the RGD motif but overlap with the SVVYGLR domain.