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Changes in tissue homeostasis, acquisition of invasive cell characteristics, and tumor formation can often be linked to the loss of epithelial cell polarity. In carcinogenesis, the grade of neoplasia correlates with impaired cell polarity. In Drosophila,  lethal giant larvae (lgl) ,  discs large (dlg) , and  scribble,  which are components of the epithelial apico-basal cell polarity machinery, act as tumor suppressors, and orthologs of this evolutionary conserved pathway are lost in human carcinoma with high frequency. However, a mechanistic link between neoplasia and vertebrate orthologs of these tumor-suppressor genes remains to be fully explored at the organismal level. Here, we show that the  pen/lgl2  mutant phenotype shares two key cellular and molecular features of mammalian malignancy: cell autonomous epidermal neoplasia and epithelial-to-mesenchymal-transition (EMT) of basal epidermal cells including the differential expression of several regulators of EMT. Further, we found that epidermal neoplasia and EMT in  pen/lgl2  mutant epidermal cells is promoted by ErbB signalling, a pathway of high significance in human carcinomas. Intriguingly, EMT in the  pen/lgl2  mutant is facilitated specifically by ErbB2 mediated E-cadherin mislocalization and not via canonical  snail –dependent down-regulation of  E-cadherin  expression. Our data reveal that  pen/lgl2  functions as a tumor suppressor gene in vertebrates, establishing zebrafish  pen/lgl2  mutants as a valuable cancer model.

Lgl2 Executes Its Function as a Tumor Suppressor by Regulating ErbB Signaling in the Zebrafish Epidermis