E-Cadherin Loss Promotes Squamous Cell Carcinoma Development through Dab-2 Down-regulation

Objectives: Loss of E-cadherin-mediated cell-cell contact is linked to advanced stages of Squamous Cell Carcinoma (SCC), however, the mechanisms that regulate the transition of a premalignant lesion to SCC are still elusive. Disabled-2 (Dab-2) is a candidate to regulate this transition by controlling the trafficking of surface proteins that are involved in cell adhesion and growth factor signaling. Furthermore, decreased Dab-2 expression is found in prostate, lung, breast and nasopharyngeal carcinomas. Here we investigated the effect of E-cadherin loss on Dab-2 expression in SCC cells in three-dimensional (3D) tissue models of skin and oral precancer.

Methods: Bioengineered human skin-equivalents were generated by seeding E-cadherin-suppressed or E-cadherin-competent SCC cells onto fibroblasts-populated collagen gels. Dab-2 expression levels were determined by immunoblotting. Tissue morphology and Dab-2 expression were analyzed by H&E, immunohistochemistry and immunofluorescence staining of tissues and SCC tumors generated following surface transplantation of these tissues to mice.

Results: In 2D cultures and 3D tissues, Dab-2 expression is decreased in E-cadherin-suppressed cells when compared to E-cadherin-competent cells. In SCC tumors, Dab-2 expression is closely associated with the degree of differentiation of these tumors. Low-grade tumors harboring E-cadherin-competent cells demonstrated Dab-2-positive, well differentiated sheets of cells. In contrast, high-grade tumors harboring E-cadherin-suppressed cells demonstrated Dab-2-negative, poorly differentiated tumor cell sheets and invasive cell clusters in the mouse stroma.   

Conclusions: This study provides new insights into the functional consequences of altered E-cadherin-mediated cell-cell adhesion in the early stages of SCC development. It suggests that the tumor-promoting effect of E-cadherin suppression is associated with decreased Dab-2 expression, an event that can in turn promote, at least in part, the tumorigenesity of E-cadherin-suppressed SCC tumor cells. These findings imply that manipulating Dab-2 expression in epithelial cells with neoplastic potential may inhibit SCC development.

A “Tufts Collaborates!” grant awarded to Drs. Alt-Holland and Baleja funded this study.