Abstract 4992: Spontaneous development of lung adenocarcinoma in the Cadm1 gene-deficient mice

Abstract

Abstract Aberration of cell adhesion is a critical step in the development and progression of human tumors. A tumor suppressor gene, CADM1(Cell adhesion molecule 1)/TSLC1(Tumor suppressor in lung cancer 1), was originally identified in non-small cell lung cancer (NSCLC) by its tumor suppressor activity in nude mice. CADM1 encodes an immunoglobulin superfamily cell adhesion molecule which is expressed in the brain, testis, lung and various other epithelial tissues. In normal polarized epithelia, CADM1 is expressed along the lateral membrane and associates in the cytoplasm with a member of 4.1-family proteins carrying actin-binding activity and a member of the membrane scaffold proteins, MAGuKs, carrying PDZ-domains. On the other hand, CADM1 is inactivated by loss of the chromosomal fragment and/or methylation of the gene promoter in 30-60% of various human cancers, including NSCLC. Here, we demonstrate that CADM1 expressing cell lines, HEK293 and Caco-2, lose their epithelia-like cell structure and show flat morphology with immature cell adhesion when the CADM1 function is abrogated by RNAi. CADM1-binding proteins, 4.1B and MPP2, as well as E-cadherin and ZO-1, are mislocalized from the membrane in HEK293 cells. Loss of CADM1 is also correlated with the transformed phenotype of cancer cells, suggesting that CADM1 is involved in the formation of epithelia-like cell structure with 4.1B and MPPs, while loss of its function could cause morphological transformation of cancer cells. To further understand the physiological roles of CADM1, we have generated Cadm1/Tslc1 gene-deficient mice and have found that Cadm1−/− male mice are infertile due to the disruption of cell adhesion between the immature spermatocytes and Sertoli cells. Here, we also demonstrate that more than 30% of Cadm1−/− mice developed lung adenomas or adenocarcinomas spontaneously at 15 months of age. In the tumors, normal alveolar structure was completely replaced by the tumor cells with atypical nuclei. Lung tumors also developed in Cadm1+/− mice at 18 months of age through the second hit of the Cadm1 gene by the promoter methylation or loss of the gene fragment, indicating that CADM1 cascade is critical to lung tumor suppression. Immunohistochemical study revealed that the membrane localization of 4.1N and CADM4, another member of CADM family proteins expressed in the lung, was abrogated in the tumors but not in the normal epithelia, suggesting that the disruption of the CADM-4.1 cascade of cell adhesion is prerequisite to lung tumor formation. Furthermore, several oncogenic signal transduction cascades were activated in these tumors. These results suggest that CADM1 is involved in lung tumor suppression through the maintenance of cell adhesion machinery as well as suppression of the growth factor cascades. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 4992.