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Invadopodia degrade ECM in the G1 phase of the cell cycle

Battuya Bayarmagnai, Louisiane Perrin, Kamyar Esmaeili Pourfarhangi, Bojana Gligorijevic
doi: https://doi.org/10.1101/412916
Battuya Bayarmagnai
1Department of Bioengineering, Temple University, Philadelphia PA
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Louisiane Perrin
1Department of Bioengineering, Temple University, Philadelphia PA
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Kamyar Esmaeili Pourfarhangi
1Department of Bioengineering, Temple University, Philadelphia PA
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Bojana Gligorijevic
1Department of Bioengineering, Temple University, Philadelphia PA
2Cancer Biology Program, Fox Chase Cancer Center, Philadelphia PA
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  • For correspondence: bojana.gligorijevic@temple.edu
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Abstract

Invadopodia are cancer cell protrusions rich in structural proteins (e.g. Tks5, cortactin) and proteases (e.g. MT1-MMP) and are responsible for degradation of the extracellular matrix (ECM). Tumor cell invasion and metastasis require cancer cells to be both proliferative and invasive, i.e. migrate through the tissue and assemble invadopodia. While several studies addressed how cell motility parameters change throughout the cell cycle, the relationship between invadopodia and cell cycle progression has not been elucidated. In this study, using invadopodia- and cell cycle- fluorescent markers, we show in 2D and 3D cell cultures, as well as in vivo, that breast carcinoma cells assemble invadopodia and invade into the surrounding ECM preferentially during the G1 phase of the cell cycle. Cells synchronized in the G0/G1 phase of the cell cycle degrade at significantly higher levels during the first 20 hours post-synchronization release. Consistent with this, mRNA and protein levels of the invadopodia key components, cortactin and MT1-MMP, peak at 14 hours post-release. Cell cycle progression is faster in cells in which invadopodia are abolished (by Tks5 knockdown), evidenced by earlier induction of cyclins A and B. A close look at the regulators of G1 revealed that the overexpression of p27kip1, but not p21cip1, causes faster turnover of invadopodia and increased ECM degradation. Furthermore, both endogenous and over-expressed p27kip1 localizes to the sites of invadopodia assembly. Taken together, these findings suggest that invadopodia function is tightly linked to cell cycle progression and is controlled by specific cell cycle regulators. Our results caution that this coordination between invasion and cell cycle must be considered when designing effective chemotherapies.

  • List of Abbreviations

    2D
    Two-dimensional
    3D
    Three-dimensional
    4D
    Four-dimensional
    BSA
    Bovine serum albumin
    CDK
    Cyclin-dependent kinase
    CKI
    Cyclin-dependent kinase inhibitor
    CMV
    Cytomegalovirus
    DAPI
    4’,6-diamidino-2-phenylindole
    DMSO
    Dimethyl sulfoxide
    ECM
    Extracellular matrix
    EDTA
    Ethylenediaminetetraacetic acid
    FACS
    Fluorescence-activated cell sorting
    FBS
    Fetal bovine serum
    FUCCI
    Fluorescent Ubiquitination Cell Cycle Indicator Gem Geminin
    KD
    Knockdown
    Lov
    Lovastatin mAG mAzami Green
    Mit C
    Mitomycin C
    mKO2
    mKusabira Orange 2
    PAK1
    p21-activated kinase
    PBS
    Phosphate-buffered saline
    PI
    Propidium Iodide
    qRT-PCR
    Quantitative real-time polymerase chain reaction
    Rb
    Retinoblastoma
    RT-PCR
    Reverse transcriptase polymerase chain reaction
    SCID
    Severe combined immunodefficiency
    SDS-
    Sodium dodecyl sulfate- polyacrylamide gel
    PAGE
    electrophoresis
    Ser
    Serine
    TBST
    Tris-buffered saline- Tween 20
    Thr
    Threonine
    Tyr
    Tyrosine
    WT
    Wild type
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    Posted September 27, 2018.
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    Invadopodia degrade ECM in the G1 phase of the cell cycle
    Battuya Bayarmagnai, Louisiane Perrin, Kamyar Esmaeili Pourfarhangi, Bojana Gligorijevic
    bioRxiv 412916; doi: https://doi.org/10.1101/412916
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    Invadopodia degrade ECM in the G1 phase of the cell cycle
    Battuya Bayarmagnai, Louisiane Perrin, Kamyar Esmaeili Pourfarhangi, Bojana Gligorijevic
    bioRxiv 412916; doi: https://doi.org/10.1101/412916

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