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

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.