Mechanisms of cancer cell migration and invasion

Most critical for late-stage cancer is the metastasis process, which is responsible for up to 90% of cancer mortality, but whose underlying molecular mechanisms are incompletely understood. Tumor cell invasion includes the cross-talk of several pathways and little is known how these interactions affect this process, evel less in the connection of tumor cells and their tumor microenvironment. To analyse these cross-talk events, we have previously developed a method called combinatorial RNAi and investigated the contribution of different signalling intermediates downstream of ErbB2, i.e. Akt1 and MEK1 in the invasive phenotype of cells (Sahin 2007). More recently, several miRNAs have been reported to be involved in the regulation of the invasive and metastasizing phenotype of cancer cells. We have demonstrated that the miR-200 family members differentially regulate EGF-driven invasion of breast cancer cells (Uhlmann 2010, Jurmeister 2012). Currently, we are studying the role of several miRNAs as well as different transcription factors in migratory phenotypes of breast cancer cells.


Proposed model for miR-200c-mediated regulation of stress fibers and migration/invasion. miR-200c targets FHOD1, resulting in  decreased actin polymerization and thus preventing stress fiber formation. Additionally, MRTFs are sequestered in the cytosol by increasing levels of monomeric actin, resulting in inhibition of SRF transcriptional activity and decreased expression of MLC2. Phosphorylated MLC2 is a component of active myosin, which contributes to stress fiber formation and function through cross-linking of actin filaments, and by providing contractile activity. A second miR-200c target gene, PPM1F, increases phosphorylation levels of MLC2 independently of MLC2 expression, and targeting of PPM1F might thus further enhance the effect of miR-200c on stress fiber formation (Jurmeister 2012).

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