Cell adhesion molecule 1 (CADM1), formerly called tumor suppressor in lung cancer-1 or nectin-like molecule-2, mediates nerve–mast cell attachment and communication through homophilic binding. An immunohistochemical screen showed that CADM1 is expressed in pancreatic islets. Here, we determined the cell types expressing CADM1 and examined its role in nerve–islet cell interactions.

Immunohistochemistry and double-staining immunofluorescence were performed on murine and human pancreases and on islet cell tumors (ICTs). αTC6 cells, a murine α cell line, were cultured on neurite networks of superior cervical ganglia. Neurite–αTC6 cell attachment and communication were examined after nerves were activated specifically by scorpion venom.

CADM1 was expressed in all 4 major types of islet cells, α, β, D, and pancreatic polypeptide in human beings, but primarily in α cells and in some D cells in mice. CADM1 localization was restricted to the plasma membrane. In cocultures, αTC6 cell to neurite attachment was inhibited dose-dependently by an anti-CADM1 function-blocking antibody. In response to scorpion venom–evoked nerve activation, 36% of the αTC6 cells mobilized Ca²⁺, and introduction of a CADM1-targeting siRNA reduced the fraction of responding cells to 7%. In 21 human ICTs, CADM1 was present in the plasma membrane of 7, and the others were negative for CADM1. Six of the CADM1-expressing tumors were functional hormonally, whereas all but 2 of the CADM1-negative tumors were nonfunctional (P = .0032).

CADM1 is a novel islet cell adhesion molecule mediating nerve–islet cell interactions. The strong correlation between CADM1 expression and hormonally functional phenotypes suggests that CADM1 is involved in hormone secretion from ICTs.