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TGFβ1 promotes collective invasion of oncogenically transformed intestinal organoids by inducing partial epithelial-mesenchymal transition independently of Snail1 and Zeb1

ABSTRACT: Cancer cells simultaneously featuring epithelial and mesenchymal traits appear particularly competent to invade and metastasize. However, genetic prerequisites and signaling pathways promoting such partial epithelial-to-mesenchymal transitions (EMT) remain obscure. Here we report that murine intestinal organoids with hyperactive Wnt and MAPK signaling, and mutant Trp53 are purely epithelial and non-invasive in vitro, but initiate a collective invasion program when treated with TGFβ1. Invasive organoids reciprocally interact with the extracellular matrix (ECM), and autonomously deposit and remodel components thereof. Although cells at the organoid/ECM interface shed certain epithelial characteristics, invasive organoids largely maintain epithelial gene expression while concomitantly upregulating a mesenchymal program. TGFβ1-induced phenotypic changes involve canonical, Smad4-dependent signaling, yet, are unimpeded by knockout of Snai1 and Zeb1 - otherwise key regulators of epithelial-to-mesenchymal transitions. The finding of TGFβ1-inducible, Snail1/Zeb1-independent collective invasion of oncogenically transformed intestinal organoids provides novel mechanistic insights and broadens the spectrum of context-dependent manifestations of partial EMT.

ORGANISM(S): Mus musculus

PROVIDER: GSE156553 | GEO | 2022/01/24

REPOSITORIES: GEO

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TGFβ1 promotes collective invasion of oncogenically transformed intestinal organoids by inducing partial epithelial-mesenchymal transition independently of Snail1 and Zeb1

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