title: The actin cross-linker Filamin/Cheerio mediates tumor malignancy downstream of JNK signaling.
abstract: Cell shape dynamics, motility, and cell proliferation all depend on the actin cytoskeleton. Malignant cancer cells hijack the actin network to grow and migrate to secondary sites. Understanding the function of actin regulators is therefore of major interest. In the present study, we identify the actin cross-linking protein Filamin/Cheerio (Cher) as a mediator of malignancy in genetically defined Drosophila tumors. We show that in invasive tumors, resulting from cooperation of activated Ras with disrupted epithelial cell polarity, Cher is upregulated in a Jun N-terminal kinase (JNK)-dependent manner. Although dispensable in normal epithelium, Cher becomes required in the tumor cells for their growth and invasiveness. When deprived of Cher, these tumor clones lose their full potential to proliferate and breach tissue boundaries. Instead, the Cher-deficient clones remain confined within the limits of their source epithelium, permitting survival of the host animal. Through interaction with the myosin II heavy chain subunit, Cher is likely to strengthen the cortical actomyosin network and reinforce mechanical tension within the invasive tumors. Accordingly, Cher is required for aberrant expression of genes downstream of the Hippo/Yorkie signaling in the tumor tissue. Our study identifies Cher as a new target of JNK signaling that links cytoskeleton dynamics to tumor progression.
authors.affiliation: Institute for Genetics and Cologne Excellence Cluster on Cellular Stress Responses in Aging-Associated Diseases (CECAD), University of Cologne, 50674 Cologne, Germany.
authors.forename: Eva
authors.initials: E
authors.lastname: Külshammer
authors.forename: Mirka
authors.initials: M
authors.lastname: Uhlirova
mesh_terms: D000199:Actins; D000818:Animals; D002460:Cell Line; D003285:Contractile Proteins / Q000235:genetics / Q000378:metabolism*; D004330:Drosophila; D029721:Drosophila Proteins / Q000235:genetics / Q000378:metabolism; D064448:Filamins; D005434:Flow Cytometry; D047468:Immunoprecipitation; D048031:JNK Mitogen-Activated Protein Kinases / Q000235:genetics / Q000378:metabolism*; D008840:Microfilament Proteins / Q000235:genetics / Q000378:metabolism*; D024462:Myosin Type II / Q000235:genetics / Q000378:metabolism; D009369:Neoplasms / Q000235:genetics / Q000378:metabolism*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction / Q000235:genetics / Q000502:physiology*
chemical_list: D000199:Actins; D003285:Contractile Proteins; D029721:Drosophila Proteins; D064448:Filamins; D008840:Microfilament Proteins; C578664:cher protein, Drosophila; D048031:JNK Mitogen-Activated Protein Kinases; D024462:Myosin Type II