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Adipose‐derived stem cells (ADSCs) are recruited by cancer cells from the adjacent tissue, and they become an integral part of the tumor microenvironment. Here, we report that ADSCs from the long‐living, tumor‐resistant blind mole rat,  Spalax,  have a low ability to migrate toward cancer cells compared with cells from its  Rattus  counterpart. Tracking 5‐ethynyl‐2′‐deoxyuridine (EdU)‐labeled ADSCs, introduced to tumor‐bearing nude mice, toward the xenografts, we found that rat ADSCs intensively migrated and penetrated the tumors, whereas only a few  Spalax  ADSCs reached the tumors. Moreover, rat ADSCs, but not  Spalax  ADSCs, acquired endothelial‐like phenotype and incorporated in the intratumoral reticular structure resembling a vasculature. Likewise, endothelial‐like cells differentiated from  Spalax  and rat ADSCs could form capillary‐like structures; however, the tube densities were higher in rat‐derived cells. Using time‐lapse microscopy, in vitro wound‐healing, and transwell migration assays, we demonstrated the impaired motility and low polarization ability of  Spalax  ADSCs. To assess whether the phosphorylated status of myosin light chain (MLC) is involved in the decreased motility of  Spalax  ADSCs, we inhibited MLC phosphorylation by blocking of Rho‐kinase (ROCK). Inhibition of ROCK resulted in the suppression of MLC phosphorylation, acquisition of actin polarization, and activation of motility and migration of  Spalax  ADSCs. We propose that reduced ADSCs migration to cancer and poor intratumoral angiogenesis play a role in  Spalax ’s cancer resistance. Learning more about the molecular strategy of noncancerous cells in  Spalax  to resist oncogenic stimuli and maintain a nonpermissive tumor milieu may lead us to developing new cancer‐preventive strategy in humans.  Stem Cells   2018;36:1630–1642

Adipose‐Derived Stem Cells of Blind Mole Rat Spalax Exhibit Reduced Homing Ability: Molecular Mechanisms and Potential Role in Cancer Suppression