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

Elizabeth L. Zoeller, Brian Pedro, Jessica Konen, Bhakti Dwivedi, Manali Rupji, Niveda Sundararaman, Lei Wang, John R. Horton, Chaojie Zhong, Benjamin G. Barwick, Xiaodong Cheng, Elisabeth D. Martinez, Matthew P. Torres, Jeanne Kowalski, Adam I. Marcus, Paula M. Vertino

Research output: Contribution to journalArticle

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.

Original languageEnglish (US)
JournalJournal of cell science
Volume132
Issue number19
DOIs
StatePublished - Oct 9 2019

    Fingerprint

Keywords

  • Epigenetic
  • Lung cancer
  • Metastasis
  • Mutation
  • Plasticity
  • RNA-seq

ASJC Scopus subject areas

  • Cell Biology

Cite this

Zoeller, E. L., Pedro, B., Konen, J., Dwivedi, B., Rupji, M., Sundararaman, N., Wang, L., Horton, J. R., Zhong, C., Barwick, B. G., Cheng, X., Martinez, E. D., Torres, M. P., Kowalski, J., Marcus, A. I., & Vertino, P. M. (2019). Genetic heterogeneity within collective invasion packs drives leader and follower cell phenotypes. Journal of cell science, 132(19). https://doi.org/10.1242/jcs.231514