The role of matrix metalloproteinases and vimentin cooperation in cancer cell invadopodia function.

• Thesis title in Czech: Úloha kooperace matrixových metaloproteáz a vimentinu ve funkci invadopódií.
• Thesis title in English: The role of matrix metalloproteinases and vimentin cooperation in cancer cell invadopodia function.
• Academic year of topic announcement: 2018/2019
• Thesis type: dissertation
• Thesis language: angličtina
• Department: Department of Cell Biology (31-151)
• Supervisor: prof. RNDr. Jan Brábek, Ph.D.
• Author: hidden - assigned by the advisor
• Date of registration: 08.10.2018
• Date of assignment: 08.10.2018

Preliminary scope of work

Invadopodia jsou specializované buněčné protruze, kriticky důležité pro většinu způsobů nádorové invazivity a metastázování. Mezi nejdůležitější enzymy, které se účastní degradace mezibuněčné hmoty zprostředkované invadopodii, patří metaloproteinázy MT1-MMP, MMP2 a MMP9. Důležitým faktorem pro růst invadopodií a invazivitu nádorových buněk je také vimentin, protein intermediálních filament. Zvýšená hladina exprese vimentinu byla potvrzena u mnoha typů epiteliálních nádorů. Byla ukázána zásadní úloha vimentinu ve směrování pohybu nádorových buněk ve 3D prostředí prostřednictvím aktivace enzymu calpain a regulace přesunu MT1-MMP na buněčný povrch. Cílem navrhovaného projektu je objasnit transport/aktivitu MT1- MMP, enzymu vázaného na membránu, a sekretovaných enzymů MMP2 a MMP9 u nádorových buněk ve 2D i ve 3D prostředí a roli vimentinu v těchto procesech.

Preliminary scope of work in English

Invadopodia are specialized protrusions of cancer cells involved in adhesion, mechanosensing and ECM degradation, critically important for most modes of cancer cell invasiveness and metastasis. Metalloproteinases MT1-MMP, MMP-2, and MMP-9 have emerged as key
proteinases that are involved in invadopodia-mediated ECM degradation. Vimentin, an intermediate filament protein, was shown to be involved in invadopodia elongation, stimulates cancer cell invasiveness and its expression is elevated in many types of epithelial cancers.
Vimentin has also been proposed to play a pivotal role in directing cancer cell motility in 3D through calpain activation and downstream regulation of MT1-MMP surface translocation. The aim of this project is to elucidate the transport/activity of both integral membrane (MT1-MMP)
and secreted (MMP-9, MMP-2) matrix metalloproteases in cancer cells in both 2D and 3D environment and the role of vimentin in this process. To achieve this goal, we intend: to analyze the transport of MT1-MMP, MMP-2, and MMP-9 to invadopodia and sites of ECM
degradation. We also aim to examine the significance of the dynamics of VIFs in cell invasion in 3D and examine the effects of vimentin intermediate filaments dynamics on the transport and activity of MT1-MMP.