Genetic heterogeneity within collective invasion packs drives leader and follower cell phenotypes

• Type of Material: Article
• Authors: Elizabeth L. Zoeller, Emory University; Brian Pedro, Emory University; Jessica Konen, Emory University; Bhakti Dwivedi, Emory University; Manali Rupji, Emory University; Niveda Sundararaman, Georgia Institute of Technology; Lei Wang, University of Texas Southwestern; John Horton, Emory University; Chaojie Zhong, Emory University; Benjamin Barwick, Emory University; Xiaodong Cheng, Emory University; Elisabeth D. Martinez, University of Texas Southwestern; Matthew P. Torres, Georgia Institute of Technology; Jeanne Kowalski, Emory University; Adam Marcus, Emory University; Paula Vertino, Emory University
• Language: English
• Date: 2019-10-01
• Publisher: COMPANY BIOLOGISTS LTD
• Publication Version: Final Published Version
• Copyright Statement: © 2019. Published by The Company of Biologists Ltd
• Final Published Version (URL): http://dx.doi.org/10.1242/jcs.231514
• Title of Journal or Parent Work: JOURNAL OF CELL SCIENCE
• Volume: 132
• Issue: 19
• Grant/Funding Information: This project has been funded in part by National Institutes of Health (NIH) grants 2R01CA077337 (to P.M.V.), R01CA201340-01 and 1U54CA209992 (to A.I.M.), R01GM117400 (to M.P.T.), R01GM114306 (to J.R.H. and X.C.) and SPORE grant P50CA70907 (to E.D.M). Additional support was provided to M.P.T. by the Georgia Clinical & Translational Science Alliance of the National Institutes of Health under award number UL1TR002378, to E.D.M (RP160493) and J.R.H. and X.C. (RR160029) by the CPRIT Program, and to E.D.M. by The Welch Foundation (I-1878). E.L.Z. was supported by NIH Predoctoral Fellowship 1F31CA186511. B.P. was support by NIH Predoctoral Fellowship 1F31CA225049. B.G.B. was supported by postdoctoral fellowship PF-17-109-1-TBG from the American Cancer Society. Support of the Emory Integrated Genomics Core Shared Resource, the Emory University Integrated Cellular Imaging Microscopy Core, and the Biostatistics and Bioinformatics Shared Resource is provided by the Winship Cancer Institute of Emory University core grant under award number 2P30CA138292.
• Keywords: Cell Biology; Metastasis; STRUCTURAL-ANALYSIS; Science & Technology; Mutation; Life Sciences & Biomedicine; GENOMIC INSTABILITY; TISSUE MIGRATION; HISTONE DEMETHYLASE; RNA-seq; ACTIN-RELATED PROTEIN-2; Epigenetic; LYSINE DEMETHYLASE 5B; EPITHELIAL-MESENCHYMAL TRANSITION; INTRATUMOR HETEROGENEITY; Plasticity; SMALL-MOLECULE INHIBITORS; Lung cancer; ARP2/3 COMPLEX
• Research Categories: Health Sciences, Oncology; Biology, Cell

Abstract

Collective invasion, the coordinated movement of cohesive packs of cells, has become recognized as a major mode of metastasis for solid tumors. These packs are phenotypically heterogeneous and include specialized cells that lead the invasive pack and others that follow behind. To better understand how these unique cell types cooperate to facilitate collective invasion, we analyzed transcriptomic sequence variation between leader and follower populations isolated from the H1299 non-small cell lung cancer cell line using an image-guided selection technique. We now identify 14 expressed mutations that are selectively enriched in leader or follower cells, suggesting a novel link between genomic and phenotypic heterogeneity within a collectively invading tumor cell population. Functional characterization of two phenotype-specific candidate mutations showed that ARP3 enhances collective invasion by promoting the leader cell phenotype and that wild-type KDM5B suppresses chain-like cooperative behavior. These results demonstrate an important role for distinct genetic variants in establishing leader and follower phenotypes and highlight the necessity of maintaining a capacity for phenotypic plasticity during collective cancer invasion.