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KRas-transformed epithelia cells invade and partially dedifferentiate by basal cell extrusion

Research output: Contribution to journalArticlepeer-review

John Fadul, Teresa Zulueta-Coarasa, Gloria M. Slattum, Nadja M. Redd, Mauricio Franco Jin, Michael J. Redd, Stephan Daetwyler, Danielle Hedeen, Jan Huisken, Jody Rosenblatt

Original languageEnglish
Article number7180
JournalNature Communications
Issue number1
PublishedDec 2021

Bibliographical note

Funding Information: We thank Adam Gardner for early studies that were not included in this report; Channing Der, George Eisenhoffer, Conan Kinsey, and David Grunwald for plasmids to construct KRas and cMyc expression vectors; Kristen Kwan for Tol2kit reagents and help; Rodney Stewart for the p53mut zebrafish line and snai1b probe plasmid; and Masa Tada for the ZO-1 antibody. We thank Simon Hughes, Claudia Linker and Vikki Williams-Ward for technical help and reagents for in situ hybridization, Russell Bell for assistance in graphing Fig. 2C, and Minna Roh-Johnson and James Gagnon for helpful feedback on our manuscript. A National Institutes of Health R01GM102169 and a Howard Hughes Faculty Scholar Award 55108560 to J.R., EMBO Long-Term Fellowships to T.Z.C. ALTF 1130-2018 and G.M.S. ALTF 1078-2015 and P30 CA042014 awarded to Huntsman Cancer Institute core facilities supported this work. We thank the University of Utah zebrafish and fluorescence microscopy cores, the King’s College London zebrafish facility and Nikon Imaging Centre, and the Max Planck Institute of Molecular Cell Biology and Genetics Light Fluorescent Microscopy Facility. An NCRR Shared Equipment Grant #1S10RR024761-01 paid for microscopy equipment. Publisher Copyright: © 2021, The Author(s).

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Metastasis is the main cause of carcinoma-related death, yet we know little about how it initiates due to our inability to visualize stochastic invasion events. Classical models suggest that cells accumulate mutations that first drive formation of a primary mass, and then downregulate epithelia-specific genes to cause invasion and metastasis. Here, using transparent zebrafish epidermis to model simple epithelia, we can directly image invasion. We find that KRas-transformation, implicated in early carcinogenesis steps, directly drives cell invasion by hijacking a process epithelia normally use to promote death-cell extrusion. Cells invading by basal cell extrusion simultaneously pinch off their apical epithelial determinants, endowing new plasticity. Following invasion, cells divide, enter the bloodstream, and differentiate into stromal, neuronal-like, and other cell types. Yet, only invading KRasV12 cells deficient in p53 survive and form internal masses. Together, we demonstrate that KRas-transformation alone causes cell invasion and partial dedifferentiation, independently of mass formation.

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