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

Abstract

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.

Author Summary

Metastasis, the dissemination and growth of tumor cells in organs distinct from which they originated, is the most common cause of cancer-related death. Accumulating evidence indicates that an individual's genetic background, the heritable complement of genetic variations that distinguish individuals, not only contributes to overall cancer risk, but also specifically influences metastatic potential. Using a mouse model of metastatic breast cancer and complex genetic analysis, we have identified Cadm1 as a metastasis susceptibility gene. Cadm1 was previously identified as a tumor suppressor in lung adenocarcinoma, and reductions in its expression have been associated with poor survival in numerous cancer types. In this manuscript, we use in vivo modeling to show that high expression of Cadm1 inhibits pulmonary metastasis, while knockdown of Cadm1 promotes the metastatic capability of tumor cells. We further show that the metastasis-suppressive effect of Cadm1 expression is lost in mice lacking T cell–mediated immunity and that this effect is partially mediated by CD8 ⁺ T-lymphocytes. Our data suggest that the inverse correlation between Cadm1 expression and disease-free survival in humans is a result of a metastasis-suppressive interaction of Cadm1 with the cell-mediated immunity.