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C/EBP? is crucial determinant of epithelial maintenance by preventing epithelial-to-mesenchymal transition.

ABSTRACT: Extracellular signals such as TGF-? can induce epithelial-to-mesenchymal transition (EMT) in cancers of epithelial origin, promoting molecular and phenotypical changes resulting in pro-metastatic characteristics. We identified C/EBP? as one of the most TGF-?-mediated downregulated transcription factors in human mammary epithelial cells. C/EBP? expression prevents TGF-?-driven EMT by inhibiting expression of known EMT factors. Depletion of C/EBP? is sufficient to induce mesenchymal-like morphology and molecular features, while cells that had undergone TGF-?-induced EMT reverted to an epithelial-like state upon C/EBP? re-expression. In vivo, mice injected with C/EBP?-expressing breast tumor organoids display a dramatic reduction of metastatic lesions. Collectively, our results show that C/EBP? is required for maintaining epithelial homeostasis by repressing the expression of key mesenchymal markers, thereby preventing EMT-mediated tumorigenesis. These data suggest that C/EBP? is a master epithelial "gatekeeper" whose expression is required to prevent unwarranted mesenchymal transition, supporting an important role for EMT in mediating breast cancer metastasis.

SUBMITTER: Lourenco AR

PROVIDER: S-EPMC7005738 | biostudies-literature | 2020 Feb

REPOSITORIES: biostudies-literature

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C/EBPɑ is crucial determinant of epithelial maintenance by preventing epithelial-to-mesenchymal transition.

Lourenço Ana Rita AR Roukens M Guy MG Seinstra Danielle D Frederiks Cynthia L CL Pals Cornelieke E CE Vervoort Stephin J SJ Margarido Andreia S AS van Rheenen Jacco J Coffer Paul J PJ

Nature communications 20200207 1

Extracellular signals such as TGF-β can induce epithelial-to-mesenchymal transition (EMT) in cancers of epithelial origin, promoting molecular and phenotypical changes resulting in pro-metastatic characteristics. We identified C/EBPα as one of the most TGF-β-mediated downregulated transcription factors in human mammary epithelial cells. C/EBPα expression prevents TGF-β-driven EMT by inhibiting expression of known EMT factors. Depletion of C/EBPα is sufficient to induce mesenchymal-like morpholog ...[more]

PMID: 32034145

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Project description:DCLK1 and Lgr5 have recently been identified as markers of quiescent and cycling stem cells in the small intestinal crypts, respectively. Epithelial-mesenchymal transition (EMT) is a key development program that is often activated during cancer invasion and metastasis, and also imparts a self-renewal capability to disseminating cancer cells. Utilizing the Citrobacter rodentium (CR)-induced transmissible murine colonic hyperplasia (TMCH) model, we observed a relative decrease in DCLK1 expression in the colonic crypts, with significant shift towards stromal staining at peak (12 days post infection) hyperplasia, whereas staining for Lgr5 and Msi-1 increased several fold. When hyperplasia was regressing (days 20-34), an expansion of DCLK1+ve cells in the CR-infected crypts compared with that seen in uninfected control was recorded. Purified colonic crypt cells exhibiting epigenetic modulation of the transforming growth factor-? (TGF?), Wnt and Notch pathways on 12 or 34 days post infection formed monolayers in vitro, and underwent trans-differentiation into fibroblast-like cells that stained positive for vimentin, fibronectin and DCLK1. These cells when trypsinized and regrown in soft agar, formed colonospheres/organoids that developed into crypt-like structures (colonoids) in Matrigel and stained positive for DCLK1. Mice exhibiting 12 or 34 days of TMCH were given azoxymethane once for 8?h (Gp1) or weekly for 3 weeks (Gp2), and subjected to crypt isolation. Crypt cells from Gp1 animals formed monolayers as well as colonospheres in soft agar and nodules/tumors in nude mice. Crypt cells isolated from Gp2 animals failed to form the monolayers, but developed into colonospheres in soft agar and nodules/tumors in nude mice. Thus, both hyperplasia and increased presence of DCLK1+ve cells promote cellular transformation in response to a second hit. The TMCH model, therefore, provides an excellent template to study how alterations in intestinal stem cells promote trans-differentiation, crypt regeneration or colon carcinogenesis following bacterial infection.

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C/EBP? is crucial determinant of epithelial maintenance by preventing epithelial-to-mesenchymal transition.

Publications

C/EBPɑ is crucial determinant of epithelial maintenance by preventing epithelial-to-mesenchymal transition.

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