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

Specialized leader cells use stable filopodia to create linear fibronectin tracks to promote collective cancer invasion. Tumor heterogeneity drives disease progression, treatment resistance, and patient relapse, yet remains largely underexplored in invasion and metastasis. Here, we investigated hete...

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Published inScience advances Vol. 6; no. 30; p. eaaz6197
Main Authors Summerbell, Emily R., Mouw, Janna K., Bell, Joshua S. K., Knippler, Christina M., Pedro, Brian, Arnst, Jamie L., Khatib, Tala O., Commander, Rachel, Barwick, Benjamin G., Konen, Jessica, Dwivedi, Bhakti, Seby, Sandra, Kowalski, Jeanne, Vertino, Paula M., Marcus, Adam I.
Format Journal Article
LanguageEnglish
Published United States American Association for the Advancement of Science 01.07.2020
Subjects
Cancer
Cell Biology
SciAdv r-articles
Online AccessGet full text
ISSN2375-2548
2375-2548
DOI10.1126/sciadv.aaz6197

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Abstract Specialized leader cells use stable filopodia to create linear fibronectin tracks to promote collective cancer invasion. 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.
AbstractList 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.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.
Specialized leader cells use stable filopodia to create linear fibronectin tracks to promote collective cancer invasion. 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.
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 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 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.
Author Seby, Sandra
Mouw, Janna K.
Konen, Jessica
Commander, Rachel
Pedro, Brian
Arnst, Jamie L.
Khatib, Tala O.
Kowalski, Jeanne
Barwick, Benjamin G.
Vertino, Paula M.
Bell, Joshua S. K.
Knippler, Christina M.
Dwivedi, Bhakti
Marcus, Adam I.
Summerbell, Emily R.
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Present address: Tempus Labs Inc., Chicago, IL, USA.
Present address: Department of Oncology, The University of Texas at Austin, Dell Medical School, Austin, TX, USA.
These authors contributed equally to this work.
Present address: Department of Thoracic/Head and Neck Medical Oncology, University of Texas MD Anderson Cancer Center, Houston, TX, USA.
Present address: Wilmot Cancer Institute, Rochester, NY, USA.
Present address: Department of Biomedical Genetics, University of Rochester School of Medicine and Dentistry, Rochester, NY, USA.
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Snippet Specialized leader cells use stable filopodia to create linear fibronectin tracks to promote collective cancer invasion. Tumor heterogeneity drives disease...
Tumor heterogeneity drives disease progression, treatment resistance, and patient relapse, yet remains largely underexplored in invasion and metastasis. Here,...
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SubjectTerms Cancer
Cell Biology
SciAdv r-articles
Title Epigenetically heterogeneous tumor cells direct collective invasion through filopodia-driven fibronectin micropatterning
URI https://www.ncbi.nlm.nih.gov/pubmed/32832657
https://www.proquest.com/docview/2436877146
https://pubmed.ncbi.nlm.nih.gov/PMC7439406
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