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 fourteen 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 shows 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.
Genetic heterogeneity within collective invasion packs drives leader and follower cell phenotypes
Contributed equally to this work
Present address: Department of Thoracic/Head and Neck Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030
Present address: Department of Biomedical Genetics, University of Rochester Medical Center, Rochester, NY, 14642
Currently Viewing Accepted Manuscript - Newer Version Available
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; Genetic heterogeneity within collective invasion packs drives leader and follower cell phenotypes. J Cell Sci 2019; jcs.231514. doi: https://doi.org/10.1242/jcs.231514
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