Many “nonmetastatic” cancers have spawned undetectable metastases before diagnosis. Eventual outgrowth of these microscopic lesions causes metastatic relapse and death, yet the events that dictate when and how micrometastases convert to overt metastases are largely unknown. We report that macrophage-stimulating protein and its receptor, Ron, are key mediators in conversion of micrometastases to bona fide metastatic lesions through immune suppression. Genetic deletion of Ron tyrosine kinase activity specifically in the host profoundly blocked metastasis. Our data show that loss of Ron function promotes an effective antitumor CD8⁺ T-cell response, which specifically inhibits outgrowth of seeded metastatic colonies. Treatment of mice with a Ron-selective kinase inhibitor prevented outgrowth of lung metastasis, even when administered after micrometastatic colonies had already been established. Our findings indicate that Ron inhibitors may hold potential to specifically prevent outgrowth of micrometastases in patients with cancer in the adjuvant setting.

Significance: Our data shed new light on an understudied, yet critically important aspect of metastasis: the conversion of clinically undetectable micrometastatic tumor cells to overt metastases that eventually cause death of the patient. Our work shows that Ron inhibition can significantly reduce metastatic outgrowth, even when administered after metastatic colonies are established. Cancer Discov; 3(7); 751–60. ©2013 AACR.

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