Abstract 4509: Overexpression of CADM1 enhances malignant features of small-cell lung cancer

Abstract

Abstract Small-cell lung cancer (SCLC) is one of the representative intractable cancers with the 5-year survival of less than 10 %. Novel approaches to the treatment of SCLC are required because recurrence arises inevitably after the initial chemotherapy. CADM1 was originally identified as a tumor suppressor of non-small cell lung cancer (NSCLC) which encodes a member of immunoglobulin superfamily cell adhesion molecules. CADM1 consists of an extracellular domain with three immunoglobulin-like loops, a trans-membrane domain and a short cytoplasmic domain containing a protein 4.1-binding motif (4.1BM) and a PDZ-II-binding motif. We have reported that CADM1 is highly expressed in 90% of human SCLC cell lines and promotes subcutaneous tumor formation of SCLC cells in nude mice. In this study, we performed clinicopathological evaluation of CADM1 in SCLC and analyzed the molecular mechanisms of malignant progression of SCLC by overexpressing CADM1. Firstly, we performed immunohistochemical analysis of CADM1 expression in high-grade neuroendocrine tumor (HGNEC) of the lung, including SCLC and large cell neuroendocrine carcinoma (LCNEC). We found that CADM1 protein was expressed in 75% (33/44) of SCLC tumors and correlated with the nodal involvement in lung HGENC. To understand pathological significance of CADM1 overexpression in SCLC, we introduced a full-length CADM1 and its mutants in the extracellular or intracellular domain into SCLC cells, SBC5, lacking endogenous CADM1 expression and assessed their malignant features in comparison with control SBC5 cells. CADM1 expression significantly enhanced colony formation in soft agar and subcutaneous tumor formation in nude mice of SBC5, whereas a mutant in 4.1BM did not. Then, we screened chemical library of 170 small molecules of known function to identify compounds which inhibit anchorage-independent growth of SCLC cells enhanced by CADM1. Inhibitors of PI3K, Akt and PKA significantly suppressed cell growth of SBC5, suggesting that CADM1 activates PI3K/Akt and PKA signaling pathways through its 4.1BM and promotes anchorage-independent growth of SCLC cells. We also found that orthotopic injection of NCI-N417 cells overexpressing CADM1 into the lung of nude mice significantly enhanced their metastasis to mediastinal lymph nodes. These results suggest that CADM1 enhances tumor growth and metastasis of SCLC cells probably by activating PI3K/Akt and PKA pathways through its binding proteins at 4.1BM. Citation Format: Toko Funaki, Takeshi Ito, Yoshinori Murakami. Overexpression of CADM1 enhances malignant features of small-cell lung cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 4509.