Integrated study of the effects of epithelial-mesenchymal transition on cell mechanics, mitotic rounding and proliferation in tumor spheroids

• Applicant: Professorin Dr. Elisabeth Fischer-Friedrich
• Subject Area: Biophysics
• Term: since 2021
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 468266561

Animal cells need to acquire a round shape to provide space for the mitotic spindle in order to undergo mitosis successfully. This mitotic rounding relies on mechanical deformation of surrounding tissue and is driven by forces emanating from actomyosin contractility of the cellular actin cortex. Failure of mitotic rounding can significantly delay mitosis or even lead to cell death.Cancer cells are able to maintain successful mitosis in mechanically challenging environments such as the increasingly crowded environment of a growing tumor. Thus, it has been hypothesized that the actin cortex of cancer cells exhibits oncogenic adaptations that allow for ongoing mitotic rounding and division inside increasingly dense tumor tissue. Epithelial Mesenchymal Transition (EMT) is a cellular transformation which was shown to be a hallmark in cancer progression. It is commonly linked to the early steps in metastasis promoting cell migration and cancer cell invasiveness. In preliminary work, we could show that EMT gives rise to opposite cell-mechanical changes in interphase and mitosis in non-adherent breast epithelial cells. While interphase cells become softer and less contractile, mitotic cells become stiffer and more contractile after EMT. These cell-mechanical changes suggest enhanced mitotic rounding strength after EMT. This conjecture is supported by our findings of increased mitotic roundness and increased proliferation in mechanically confined post-EMT tumor spheroids. In the proposed project, we aim to further test our hypothesis that EMT-induced changes of cortical mechanics and mitotic rounding give rise to enhanced cell proliferation in tumor spheroids in mechanical confinement. In addition, we aim to elucidate cellular signaling pathways involved in the generation of the EMT-induced cortex-mechanical phenotype. Motivated by our previous findings, we will in particular, elucidate the role of RhoA and Rac1 activity changes. The insight of this research may reveal a new scheme of how EMT promotes growth of carcinoma in the body. In summary, our findings will not only provide high impact results to the field of cell biology but will also identify potential new targets for cancer therapeutics.

• DFG Programme: Research Grants