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

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

Stem cell fate in cancer growth, progression and therapy resistance

Although we have come a long way in our understanding of the signals that drive cancer growth, and how these signals can be targeted, effective control of this disease remains a key scientific and medical challenge. The therapy resistance and relapse that are commonly seen are driven in large part by the inherent heterogeneity within cancers that allows drugs to effectively eliminate some, but not all, malignant cells. Here, we focus on the fundamental drivers of this heterogeneity by examining emerging evidence that shows that these traits are often controlled by the disruption of normal cell fate and aberrant adoption of stem cell signals. We discuss how undifferentiated cells are preferentially primed for transformation and often serve as the cell of origin for cancers. We also consider evidence showing that activation of stem cell programmes in cancers can lead to progression, therapy resistance and metastatic growth and that targeting these attributes may enable better control over a difficult disease