Invasive cells at the tumor front express L1 (brown).

In cancer cells, β-catenin localizes to the nucleus where, together with LEF/TCF factors, it induces hyperactivation of numerous genes involved in carcinogenesis. Previously, researchers thought that most of the β-catenin/TCF target genes were active early in disease progression, but the transcription complex appears to work late in the process as well. Gavert et al. (on page 633) find that β-catenin/TCF induces expression of L1, a transmembrane adhesion protein normally expressed in migrating neurons, in invading colon cancer cells.

Colon cancer cells grown at low but not high densities express high levels of L1. Because 90% of colon cancer cells have aberrant β-catenin signaling, the team tested the response of L1 promoter constructs to β-catenin siRNA and dominant-negative TCF proteins and found that the β-catenin/TCF complex activates the L1 gene. Furthermore, L1 expression increased cell motility and matrix invasion in fibroblasts and colon cancer cells. In patient samples, L1 was expressed only at the invading margins of tumors, not in the cell-dense center.

L1 expression in both cell culture and patient samples was accompanied by expression of ADAM10, a metalloproteinase known to clip the extracellular domain of L1. The team is currently investigating whether ADAM10 is also directly regulated by β-catenin/TCF, and how L1 confers the invasive properties on tumor cells.