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

John Fadul, Teresa Zulueta-Coarasa, Gloria M. Slattum, Nadja M. Redd, Mauricio Franco Jin, Michael J. Redd, Stephan Daetwyler, Danielle Hedeen, Jan Huisken and Jody Rosenblatt ()
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John Fadul: King’s College London
Teresa Zulueta-Coarasa: King’s College London
Gloria M. Slattum: University of Utah
Nadja M. Redd: ARUP Laboratories
Mauricio Franco Jin: University of Utah
Michael J. Redd: University College London
Stephan Daetwyler: UT Southwestern Medical Center
Danielle Hedeen: University of Utah
Jan Huisken: University of Wisconsin
Jody Rosenblatt: King’s College London

Nature Communications, 2021, vol. 12, issue 1, 1-9

Abstract: Abstract 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.

Date: 2021
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DOI: 10.1038/s41467-021-27513-z

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