Dorsoventral polarity directs cell responses to migration track geometries

Emily O Wisniewski; Panagiotis Mistriotis; Kaustav Bera; Robert A Law; Jitao Zhang; Milos Nikolic; Michael Weiger; Maria Parlani; Soontorn Tuntithavornwat; Alexandros Afthinos; Runchen Zhao; Denis Wirtz; Petr Kalab; Giuliano Scarcelli; Peter Friedl; Konstantinos Konstantopoulos

doi:10.1126/sciadv.aba6505

Dorsoventral polarity directs cell responses to migration track geometries

Sci Adv. 2020 Jul 31;6(31):eaba6505. doi: 10.1126/sciadv.aba6505. eCollection 2020 Jul.

Authors

Emily O Wisniewski^{1

2}, Panagiotis Mistriotis^{1

2

3}, Kaustav Bera^{1

2}, Robert A Law^{1

2}, Jitao Zhang⁴, Milos Nikolic^{4

5}, Michael Weiger⁶, Maria Parlani⁶, Soontorn Tuntithavornwat^{1

2}, Alexandros Afthinos^{1

2

7}, Runchen Zhao^{1

2}, Denis Wirtz^{1

2

8

9

10}, Petr Kalab¹, Giuliano Scarcelli⁴, Peter Friedl^{6

11

12}, Konstantinos Konstantopoulos^{1

2

8

9

10}

Affiliations

¹ Department of Chemical and Biomolecular Engineering, Johns Hopkins University, Baltimore, MD 21218, USA.
² Johns Hopkins Institute for NanoBioTechnology, Johns Hopkins University, Baltimore, MD 21218, USA.
³ Department of Chemical Engineering, Auburn University, Auburn, AL 36849, USA.
⁴ Fischell Department of Bioengineering, University of Maryland, College Park, MD 20742, USA.
⁵ Maryland Biophysics Program, Institute for Physical Science and Technology, University of Maryland, College Park, MD 20742, USA.
⁶ Department of Genitourinary Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
⁷ Department of Neurology, Johns Hopkins University, Baltimore, MD 21287, USA.
⁸ Johns Hopkins Physical Sciences Oncology Center, Johns Hopkins University, Baltimore, MD 21218, USA.
⁹ Department of Biomedical Engineering, Johns Hopkins University, Baltimore, MD 21218, USA.
¹⁰ Department of Oncology, Johns Hopkins University, Baltimore, MD 21205, USA.
¹¹ Department of Cell Biology, Radboud Institute for Molecular Life Sciences, Radboud University Medical Center, Nijmegen, Netherlands.
¹² Cancer Genomics Centre, 3584 Utrecht, Netherlands.

Abstract

How migrating cells differentially adapt and respond to extracellular track geometries remains unknown. Using intravital imaging, we demonstrate that invading cells exhibit dorsoventral (top-to-bottom) polarity in vivo. To investigate the impact of dorsoventral polarity on cell locomotion through different confining geometries, we fabricated microchannels of fixed cross-sectional area, albeit with distinct aspect ratios. Vertical confinement, exerted along the dorsoventral polarity axis, induces myosin II-dependent nuclear stiffening, which results in RhoA hyperactivation at the cell poles and slow bleb-based migration. In lateral confinement, directed perpendicularly to the dorsoventral polarity axis, the absence of perinuclear myosin II fails to increase nuclear stiffness. Hence, cells maintain basal RhoA activity and display faster mesenchymal migration. In summary, by integrating microfabrication, imaging techniques, and intravital microscopy, we demonstrate that dorsoventral polarity, observed in vivo and in vitro, directs cell responses in confinement by spatially tuning RhoA activity, which controls bleb-based versus mesenchymal migration.

Copyright © 2020 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works. Distributed under a Creative Commons Attribution NonCommercial License 4.0 (CC BY-NC).

Publication types

Research Support, N.I.H., Extramural
Research Support, U.S. Gov't, Non-P.H.S.
Research Support, Non-U.S. Gov't

Abstract

Publication types

Grants and funding