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ECM cross-linking regulates invadopodia dynamics

Kamyar Esmaeili, Aviv Bergman, Bojana Gligorijevic
doi: https://doi.org/10.1101/198580
Kamyar Esmaeili
1BioEngineering Department, College of Engineering, Temple University, 1947 N 12th st, 19122 Philadelphia, PA, USA
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Aviv Bergman
2Systems & Computational Biology Department, Albert Einstein College of Medicine, 1301 Morris Park ave, 10461 Bronx, NY, USA
3Santa Fe Institute, 1399 Hyde Park Road, 87501 Santa Fe, NM, USA
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  • For correspondence: bojana@temple.edu aviv@einstein.yu.edu
Bojana Gligorijevic
1BioEngineering Department, College of Engineering, Temple University, 1947 N 12th st, 19122 Philadelphia, PA, USA
4Cancer Biology Program, Fox Chase Cancer Center, Philadelphia, PA, USA
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  • For correspondence: bojana@temple.edu aviv@einstein.yu.edu
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Abstract

InvadopodiInvadopodia are membrane protrusions dynamically assembled by invasive cancer cells in contact with extracellular matrix (ECM). Invadopodia are enriched for the structural proteins actin and cortactin, as well as metalloproteases such as MT1-MMP, whose function is to degrade the surrounding ECM. During metastasis, invadopodia are necessary for cancer cell intravasation and extravasation. While signaling pathways involved in the assembly and function of invadopodia are well studied, few studies address invadopodia dynamics and how the cell-ECM interactions contribute to cell invasion. Using iterative analysis based on time-lapse microscopy and mathematical modeling of invasive cancer cells, we found that cells oscillate between invadopodia presence and cell stasis, termed Invadopodia state and invadopodia absence during cell translocation, termed Migration state. Our data suggests that β1-integrin-ECM binding and ECM cross-linking control the duration of each of the two states. By changing the concentration of cross-linkers in 2D and 3D cultures, we generate ECM where 0-0.92 of total lysine residues are cross-linked. Using ECM with a range of cross-linking degrees we demonstrate that the dynamics of invadopodia-related functions have a biphasic relationship to ECM cross-linking. At intermediate levels of ECM cross-linking (0.39), cells exhibit rapid invadopodia protrusion-retraction cycles and rapid calcium spikes, which lead to more frequent MT1-MMP delivery, causing maximal invadopodia-mediated ECM degradation. In contrast, both extremely high or low levels of cross-linking lead to slower invadopodia-related dynamics and lower ECM degradation. Additionally, β1-integrin inhibition modifies dynamics of invadopodia-related functions, as well as the length of time cells spend in either of the states. Collectively, these data suggest that β1-integrin-ECM binding non-linearly translates small physical differences in extracellular environment to differences in the dynamics of cancer cell behaviors. Understanding conditions under which invadopodia can be reduced by subtle environment-targeting treatments may lead to combination therapies for preventing metastatic spread.

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Posted January 30, 2018.
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ECM cross-linking regulates invadopodia dynamics
Kamyar Esmaeili, Aviv Bergman, Bojana Gligorijevic
bioRxiv 198580; doi: https://doi.org/10.1101/198580
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ECM cross-linking regulates invadopodia dynamics
Kamyar Esmaeili, Aviv Bergman, Bojana Gligorijevic
bioRxiv 198580; doi: https://doi.org/10.1101/198580

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