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Metastasis is a complex process utilizing both tumor-cell-autonomous properties and host-derived factors, including cellular immunity. We have previously shown that germline polymorphisms can modify tumor cell metastatic capabilities through cell-autonomous mechanisms. However, how metastasis susceptibility genes interact with the tumor stroma is incompletely understood. Here, we employ a complex genetic screen to identify  Cadm1  as a novel modifier of metastasis. We demonstrate that  Cadm1  can specifically suppress metastasis without affecting primary tumor growth. Unexpectedly,  Cadm1  did not alter tumor-cell-autonomous properties such as proliferation or invasion, but required the host's adaptive immune system to affect metastasis. The metastasis-suppressing effect of  Cadm1  was lost in mice lacking T cell–mediated immunity, which was partially phenocopied by depleting CD8 +  T cells in immune-competent mice. Our data show a novel function for  Cadm1  in suppressing metastasis by sensitizing tumor cells to immune surveillance mechanisms, and this is the first report of a heritable metastasis susceptibility gene engaging tumor non-autonomous factors.

Cadm1 Is a Metastasis Susceptibility Gene That Suppresses Metastasis by Modifying Tumor Interaction with the Cell-Mediated Immunity