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.

Epithelial-mesenchymal transition leads to NK cell–mediated metastasis-specific immunosurveillance in lung cancer

“…The role of CADM1 in the evasion of immunosurveillance has never been considered as a potential mechanism for tumor suppression. Earlier studies that demonstrated the inhibition of tumor growth by CADM1 overexpression were carried out in nude mice or mice that carry functional NK cells and overlooked the role of NK cells in the observed tumor suppression (34,(52)(53)(54). Our data clearly demonstrate that CADM1 overexpression is sufficient to make cancer cells sensitive to NK cells, in vitro.…”

An integrated systems genetics screen reveals the transcriptional structure of inherited predisposition to metastatic disease

“…Intriguingly, Mir3470b overexpression appeared to have a unidirectional effect on previously identified metastasis susceptibility genes, up-regulating the pro-metastatic Brd4 short isoform (Brd4-SF) while down-regulating anti-metastatic genes: Brd4 long isoform (Brd4-LF), Rrp1b, and Cadm1 (Supplemental Fig. 43; Crawford et al 2007Crawford et al , 2008aAlsarraj et al 2011;Faraji et al 2012). Consistent with the correlative data in 67NR and 4T1 cells, the negative regulatory effect of Mir3470a/b on Cnot2 module transcripts and the changes in expression of previously identified metastasis susceptibility genes were suggestive of a pro-metastatic role for Mir3470a/b.…”

“…We have previously demonstrated that germline polymorphisms can modify gene expression patterns and result in differences in heritable metastatic susceptibility (Faraji et al 2012;Hu et al 2012;Winter et al 2012). Based on this principle, we analyzed gene expression profile data from two to seven tumors from each of the [AKXD n 3 PyMT]F 1 progeny on Affymetrix MOE430 microarrays .…”

Microenvironmental Influences on Metastasis Suppressor Expression and Function during a Metastatic Cell’s Journey

“…Originally thought of as a tumor suppressor, CADM1 can attenuate primary tumor growth in some cancer lines, including non-small cell lung cancer and breast cancer [164]. True to its role as a metastasis suppressor, CADM1 expression does not alter tumor cell-autonomous properties involving proliferation or invasion [165]. Rather, CADM1 requires the host's adaptive immune system, primarily T-cells, to suppress metastasis [165].…”

“…True to its role as a metastasis suppressor, CADM1 expression does not alter tumor cell-autonomous properties involving proliferation or invasion [165]. Rather, CADM1 requires the host's adaptive immune system, primarily T-cells, to suppress metastasis [165]. CADM1 expression is regulated largely by promoter hypermethylation, leading to loss of CADM1 expression and a more motile, EMT phenotype in metastatic lesions [166][167][168].…”