Molecular mechanisms of mechanotransduction during tumor progression

• Applicant: Professorin Dr. Mirka Uhlirova
• Subject Area: Cell Biology ; General Genetics and Functional Genome Biology
• Term: from 2014 to 2018
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 253567115

Cells within tissues are continuously exposed to mechanical cues generated by cell-cell and cell-extracellular matrix (ECM) interactions. Responses to mechanical forces include exertion of reciprocal tension through actomyosin contraction, changes in gene expression, and remodeling of the extracellular environment. The ability of cells to sense, transduce and respond to mechanical stimuli is crucial for organ development and homeostasis. Defects in mechanosensing and altered mechanotransduction have been linked to tumor formation, progression and metastasis. Deciphering the signaling and effector network that controls tensional homeostasis is, therefore, of major interest. Over the past years, our work using an established, genetically defined Drosophila tumor model has unraveled how cooperating oncogenes impact on cellular mechanobiology through deregulation of the Jun N-terminal kinase (JNK) signaling pathway. We have shown that invasiveness of clonal tumors, resulting from cooperation of activated Ras with loss of epithelial cell polarity, requires JNK-dependent up-regulation of a Matrix metalloprotease (MMP1) (Uhlirova and Bohmann, EMBO J, 2006). Recently, we have identified the actin cross-linking protein Filamin A/Cheerio (Cher) as a novel target of JNK signaling that links actin cytoskeleton dynamics to tumor progression. Although Cher is dispensable for normal Drosophila eye development, it becomes required in the epithelial tumors for their growth and invasiveness through regulating actomyosin tension (Külshammer and Uhlirova, J Cell Sci, 2013). Building on our previously published and preliminary data, this proposal aims (1) to identify mechanisms that link the actomyosin/Filamin A complex to tumor progression using Drosophila and mammalian tumor models, (2) to investigate how activated tumor stroma alters mechanotransduction and contributes to malignant progression, and (3) to define tumor- and stroma-specific expression signatures using in-depth comparative genomics. Our work will provide better understanding of how oncogene-induced alteration of the mechanoregulatory network contributes to tumor initiation, pre-malignant growth, and progression towards metastases. We believe that by bringing new insights into tumor cell and tissue mechanobiology, the proposed project will be of general importance for biomedical research.

• DFG Programme: Research Grants