Loss of Cell Adhesion Increases Tumorigenic Potential of Polarity Deficient Scribble Mutant Cells.
Epithelial polarity genes are important for maintaining tissue architecture, and regulating growth. The Drosophila neoplastic tumor suppressor gene scribble (scrib) belongs to the basolateral polarity complex. Loss of scrib results in disruption of its growth regulatory functions, and downregulation or mislocalization of Scrib is correlated to tumor growth. Somatic scribble mutant cells (scrib-) surrounded by wild-type cells undergo apoptosis, which can be prevented by introduction of secondary mutations that provide a growth advantage. Using genetic tools in Drosophila, we analyzed the phenotypic effects of loss of scrib in different growth promoting backgrounds. We investigated if a central mechanism that regulates cell adhesion governs the growth and invasive potential of scrib mutant cells. Here we show that increased proliferation, and survival abilities of scrib- cells in different genetic backgrounds affect their differentiation, and intercellular adhesion. Further, loss of scrib is sufficient to cause reduced cell survival, activation of the JNK pathway and a mild reduction of cell adhesion. Our data show that for scrib cells to induce aggressive tumor growth characterized by loss of differentiation, cell adhesion, increased proliferation and invasion, cooperative interactions that derail signaling pathways play an essential role in the mechanisms leading to tumorigenesis. Thus, our study provides new insights on the effects of loss of scrib and the modification of these effects via cooperative interactions that enhance the overall tumorigenic potential of scrib deficient cells.
Department of Biology, University of Dayton, Dayton, Ohio, United States of America.
Indrayani
I
Waghmare
Department of Biology, University of Dayton, Dayton, Ohio, United States of America.|Center for Tissue Regeneration and Engineering at Dayton (TREND), University of Dayton, Dayton, Ohio, United States of America.|Premedical Programs, University of Dayton, Dayton, Ohio, United States of America.|SupraMolecular Applied Research and Technology Center (SMART), University of Dayton, Dayton, Ohio, United States of America.
Madhuri
http://orcid.org/0000-0003-2447-6997
M
Kango-Singh
D022005:Adherens Junctions / Q000378:metabolism; D000818:Animals; D063646:Carcinogenesis / Q000473:pathology*; D002448:Cell Adhesion; D002454:Cell Differentiation; D016764:Cell Polarity; D049109:Cell Proliferation; D002470:Cell Survival; D002999:Clone Cells; D029721:Drosophila Proteins / Q000235:genetics* / Q000378:metabolism; D004331:Drosophila melanogaster / Q000166:cytology* / Q000235:genetics* / Q000254:growth & development; D004847:Epithelial Cells / Q000378:metabolism; D048031:JNK Mitogen-Activated Protein Kinases / Q000378:metabolism; D008565:Membrane Proteins; D008954:Models, Biological; D009154:Mutation / Q000235:genetics*; D015398:Signal Transduction; D025521:Tumor Suppressor Proteins / Q000235:genetics*
D029721:Drosophila Proteins; D008565:Membrane Proteins; C404683:Scrib protein, Drosophila; D025521:Tumor Suppressor Proteins; D048031:JNK Mitogen-Activated Protein Kinases