Response to tumor-derived RANKL or exposure to recombinant RANKL protein, LNRANKL, or LNNeo/LNRFP cells in the bone microenvironment may establish a premetastatic niche through three potential mechanisms: i) interaction with cancer cells to amplify downstream targets and effectors through upregulation of a host of MR TFs, such as c-Myc/Max, FoxA2, Sox2, Sox9, Oct4, NF-κB RelA, HIF1α, and Zeb1, that promote growth, survival, angiogenesis, EMT and stem and neuroendocrine-cell phenotypes that promote cancer cell growth in bone (Fig. 3). Here, MAX is linked to neoplasm.