No abstract

The initial step of organ infiltration of malignant cells is the interaction with host vascular endothelial cells, which is often mediated by specific combinations of cell adhesion molecules. Cell adhesion molecule 1 (CADM1) is overexpressed in adult T‐cell leukemia/lymphoma (ATL) and provides a cell‐surface diagnostic marker. CADM1 promotes the adhesion of ATL cells to vascular endothelial cells and multiple organ infiltration in mice. However, its binding partner on host cells has not yet been identified. In this study, we show that CADM1 promotes transendothelial migration of ATL cells in addition to the adhesion to vascular endothelial cells. Moreover, CADM1 enhances liver infiltration of mouse T‐cell lymphoma cells, EL4, after tail vein injection, whereas a CADM1 mutant lacking adhesive activity did not. Among the known CADM1‐binding proteins expressed in primary endothelial cells, only CADM1 and CADM4 could induce morphological extension of ATL cells when plated onto glass coated with these proteins. Furthermore, CADM1‐mediated liver infiltration of EL4 cells was canceled in conventional and vascular endothelium‐specific Cadm1 knockout mice, whereas it was not canceled in Cadm4 knockout mice. These results suggest that CADM1 on host vascular endothelial cells is required for organ infiltration of ATL and other T‐cell lymphomas expressing CADM1.

Molecular targeted therapies against EGFR and ALK have improved the quality of life of lung adenocarcinoma patients. However, targetable driver mutations are mainly found in thyroid transcription factor‐1 (TTF‐1)/NK2 homeobox 1 (NKX2‐1)‐positive terminal respiratory unit (TRU) types and rarely in non‐TRU types. To elucidate the molecular characteristics of the major subtypes of non‐TRU‐type adenocarcinomas, we analyzed 19 lung adenocarcinoma cell lines (11 TRU types and 8 non‐TRU types). A characteristic of non‐TRU‐type cell lines was the strong expression of TFF‐1 (trefoil factor‐1), a gastric mucosal protective factor. An immunohistochemical analysis of 238 primary lung adenocarcinomas resected at Jichi Medical University Hospital revealed that TFF‐1 was positive in 31 cases (13%). Expression of TFF‐1 was frequently detected in invasive mucinous (14/15, 93%), enteric (2/2, 100%), and colloid (1/1, 100%) adenocarcinomas, less frequent in acinar (5/24, 21%), papillary (7/120, 6%), and solid (2/43, 5%) adenocarcinomas, and negative in micropapillary (0/1, 0%), lepidic (0/23, 0%), and microinvasive adenocarcinomas or adenocarcinoma in situ (0/9, 0%). Expression of TFF‐1 correlated with the expression of HNF4‐α and MUC5AC (P < .0001, P < .0001, respectively) and inversely correlated with that of TTF‐1/NKX2‐1 (P < .0001). These results indicate that TFF‐1 is characteristically expressed in non‐TRU‐type adenocarcinomas with gastrointestinal features. The TFF‐1‐positive cases harbored KRAS mutations at a high frequency, but no EGFR or ALK mutations. Expression of TFF‐1 correlated with tumor spread through air spaces, and a poor prognosis in advanced stages. Moreover, the knockdown of TFF‐1 inhibited cell proliferation and soft‐agar colony formation and induced apoptosis in a TFF‐1‐high and KRAS‐mutated lung adenocarcinoma cell line. These results indicate that TFF‐1 is not only a biomarker, but also a potential molecular target for non‐TRU‐type lung adenocarcinomas.

Small-cell lung cancer (SCLC) is aggressive neuroendocrine cancer that accounts for approximately 15% of lung cancer. Although chemotherapy is effective for SCLC, resistant tumors develop rapidly; therefore, early detection in the initial screening and after chemotherapy is one of the critical issues in controlling SCLC progression. For this purpose, neuron-specific enolase (NSE) and pro-gastrin-releasing peptide (ProGRP) are used as tumor markers for SCLC but are not sensitive enough, especially in the early stages. Previously we found that Cell adhesion molecule 1 (CADM1) is highly expressed in SCLC, and an SCLC-specific splicing variant, CADM1v8/9, is selectively cleaved by ADAM17 protease to release the extracellular fragments. Here, we report that soluble CADM1v8/9 fragments (sCADM1v8/9) can be a serum marker of SCLC associated with poor prognosis and metastasis. Immunohistochemical analysis showed that the expression of CADM1 was observed in 83% of the resected SCLC cases and strongly correlated with that of INSM1, a marker of neuroendocrine differentiation. The high expression of CADM1 was associated with poor prognosis and nodal involvement, which was supported by experimental data showing that CADM1 promoted subcutaneous tumor growth and lymph node metastasis of SCLC cells in nude mice. Moreover, sCADM1v8/9 distinguished 47% of SCLC, including a significant portion of patients with limited disease SCLC, independent of and partly overlapped with the cases detected by ProGRP or NSE. Notably, a high amount of sCADM1v8/9 was observed in SCLC cases with liver metastasis or pleural effusion. Furthermore, serum levels of sCADM1v8/9 well reflected the change in tumor burden before and after chemotherapy. These findings indicate that detecting sCADM1v8/9 in sera would provide clinical benefits in diagnosis, follow-up, and metastasis prediction of SCLC cases. Citation Format: Takeshi Ito, Toko Funaki, Hiroko Iwanari, Goh Tanaka, Takahide Nagase, Takao Hamakubo, Yoshinori Murakami. CADM1 is a serum marker for small-cell lung cancer associated with poor prognosis and metastasis [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 3293.