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Harnessing the adaptive potential of mechanoresponsive proteins to overwhelm pancreatic cancer dissemination and invasion

Alexandra Surcel, Eric Schiffhauer, Dustin Thomas, Qingfeng Zhu, Kathleen DiNapoli, Maik Herbig, Oliver Otto, Jochen Guck, Elizabeth Jaffee, Pablo Iglesias, Robert Anders, Douglas Robinson
doi: https://doi.org/10.1101/190553
Alexandra Surcel
1Department of Cell Biology, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA
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  • For correspondence: asurcel1@jhmi.edu dnr@jhmi.edu
Eric Schiffhauer
1Department of Cell Biology, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA
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Dustin Thomas
1Department of Cell Biology, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA
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Qingfeng Zhu
1Department of Cell Biology, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA
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Kathleen DiNapoli
1Department of Cell Biology, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA
3Department of Electrical and Computer Engineering, Johns Hopkins University Whiting School of Engineering, Baltimore, MD 21218, USA
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Maik Herbig
4Biotechnology Center, TU Dresden, 01307 Dresden, Germany
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Oliver Otto
4Biotechnology Center, TU Dresden, 01307 Dresden, Germany
5Current address: Centre for Innovation Competence, Humoral Immune Reactions in Cardiovascular Diseases Biomechanics, University of Greifswald, 17489 Greifswald, Germany
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Jochen Guck
4Biotechnology Center, TU Dresden, 01307 Dresden, Germany
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Elizabeth Jaffee
6Department of Oncology, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA
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Pablo Iglesias
3Department of Electrical and Computer Engineering, Johns Hopkins University Whiting School of Engineering, Baltimore, MD 21218, USA
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Robert Anders
2Department of Pathology, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA
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Douglas Robinson
1Department of Cell Biology, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA
7Department of Pharmacology and Molecular Sciences, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA
8Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA
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  • For correspondence: asurcel1@jhmi.edu dnr@jhmi.edu
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Abstract

Metastatic disease is often characterized by altered cellular contractility and deformability, lending cells and groups of cells the flexibility to navigate through different microenvironments. This ability to change cell shape is driven in large part by the structural elements of the mechanobiome, which includes cytoskeletal proteins that sense and respond to mechanical stimuli. Here, we demonstrate that key mechanoresponsive proteins (those which accumulate in response to mechanical stress), specifically nonmuscle myosin IIA and IIC, α-actinin 4, and filamin B, are highly upregulated in pancreatic ductal adenocarcinoma cancer (PDAC) and in patient-derived pancreatic cancer cell lines. Their less responsive sister paralogs (myosin IIB, α-actinin 1, and filamin A) show a smaller dynamic range or disappear with PDAC progression. We demonstrate that these mechanoresponsive proteins directly impact cell mechanics using knock-down and overexpression cell lines. We further quantify the nonmuscle myosin II family members in patient-derived cell lines and identify a role for myosin IIC in the formation of transverse actin arcs in single cells and cortical actin belts in tissue spheroids. We harness the upregulation of myosin IIC and its impact of cytoskeletal architecture through the use of the mechanical modulator 4-hydroxyacetophenone (4-HAP), which increases myosin IIC assembly and stiffens cells. Here, 4-HAP decreases dissemination, induces cortical actin belts, and slows retrograde actin flow in spheroids. Finally, mice having undergone hemi-splenectomies with PDAC cells and then treated with 4-HAP have a reduction in liver metastases. Thus, increasing the activity of these mechanoresponsive proteins (in this case, by increasing myosin IIC assembly) to overwhelm the ability of cells to polarize and invade may be an effective strategy to improve the five-year survival rate of pancreatic cancer patients, currently hovering around 6%.

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Posted September 19, 2017.
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Harnessing the adaptive potential of mechanoresponsive proteins to overwhelm pancreatic cancer dissemination and invasion
Alexandra Surcel, Eric Schiffhauer, Dustin Thomas, Qingfeng Zhu, Kathleen DiNapoli, Maik Herbig, Oliver Otto, Jochen Guck, Elizabeth Jaffee, Pablo Iglesias, Robert Anders, Douglas Robinson
bioRxiv 190553; doi: https://doi.org/10.1101/190553
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Harnessing the adaptive potential of mechanoresponsive proteins to overwhelm pancreatic cancer dissemination and invasion
Alexandra Surcel, Eric Schiffhauer, Dustin Thomas, Qingfeng Zhu, Kathleen DiNapoli, Maik Herbig, Oliver Otto, Jochen Guck, Elizabeth Jaffee, Pablo Iglesias, Robert Anders, Douglas Robinson
bioRxiv 190553; doi: https://doi.org/10.1101/190553

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