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Author Notes:

Correspondence: aimarcu@emory.edu

Author contributions: E.R.S., J.K.M, P.M.V., and A.I.M. designed the experiments. E.R.S., J.K.M., J.L.A., C.M.K., B.P., B.G.B., T.O.K., and J.Kon. performed the experiments. E.R.S., J.S.K.B., B.G.B., B.D., S.S., and J.Kow. contributed to the bioinformatics and statistical analysis of the genomics and epigenomics data.

E.R.S., J.K.M., and R.C. drafted the manuscript. All authors provided input and feedback during manuscript preparation and edited the manuscript.

We thank G. Bassell at the Emory University for the gd2PAL-Dendra2 plasmid. We also thank R. Cheney at the UNC Chapel Hill for the GFP-MYO10 and mCherry-MYO10 plasmids and for invaluable discussions and advice concerning MYO10.

Disclosures: The authors declare no competing interests with this work.

Subjects:

Research Funding:

This work was supported by NIH NCI R01 grants 1R01CA250422, 1R01CA236369, and 5R01CA194027 (A.I.M.), R21 grant 1R21CA201744-01 (A.I.M.), U54 grant 5U54CA209992, and F31 NRSA grants 1F31CA210601 (E.R.S.), 1F31CA186676 (J.S.K.B.), 1F31CA225049 (B.P.), and 1F31CA180511 (J.K.).

In addition, research reported in this publication was supported, in part, by the following Shared Resources of Winship Cancer Institute of Emory University and NIH/NCI under the Cancer Center Support grant award number P30CA138292:

Emory University Integrated Cellular Imaging Microscopy Core, the Biostatistics and Bioinformatics Shared Resource, the Emory Integrated Genomics Core (EIGC),

Emory Integrated Proteomics Core (EIPC), and the Pediatrics/Winship Flow Cytometry Core.

Additional funding included Developmental Funds from the Winship Cancer Institute of Emory University and Postdoctoral Fellowship (PF-17-109-1-TBG) from the American Cancer Society (B.G.B.).

Keywords:

  • Science & Technology
  • Multidisciplinary Sciences
  • Science & Technology - Other Topics
  • Myosin-x
  • Intratumor heterogeneity
  • Extracellular matrix
  • Cancer
  • Migration
  • Expression
  • Integrins
  • Coexpression
  • Clusters
  • Impact

Epigenetically heterogeneous tumor cells direct collective invasion through filopodia-driven fibronectin micropatterning

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Journal Title:

Science Advances

Volume:

Volume 6, Number 30

Publisher:

, Pages eaaz6197-eaaz6197

Type of Work:

Article | Final Publisher PDF

Abstract:

Tumor heterogeneity drives disease progression, treatment resistance, and patient relapse, yet remains largely underexplored in invasion and metastasis. Here, we investigated heterogeneity within collective cancer invasion by integrating DNA methylation and gene expression analysis in rare purified lung cancer leader and follower cells. Our results showed global DNA methylation rewiring in leader cells and revealed the filopodial motor MYO10 as a critical gene at the intersection of epigenetic heterogeneity and three-dimensional (3D) collective invasion. We further identified JAG1 signaling as a previously unknown upstream activator of MYO10 expression in leader cells. Using live-cell imaging, we found that MYO10 drives filopodial persistence necessary for micropatterning extracellular fibronectin into linear tracks at the edge of 3D collective invasion exclusively in leaders. Our data fit a model where epigenetic heterogeneity and JAG1 signaling jointly drive collective cancer invasion through MYO10 up-regulation in epigenetically permissive leader cells, which induces filopodia dynamics necessary for linearized fibronectin micropatterning.

Copyright information:

© 2020 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science

This is an Open Access work distributed under the terms of the Creative Commons Attribution-NonCommercial 4.0 International License (https://creativecommons.org/licenses/by-nc/4.0/).
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