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Elife. 2017 Feb 21;6. pii: e22914. doi: 10.7554/eLife.22914.

De-repression of the RAC activator ELMO1 in cancer stem cells drives progression of TGFβ-deficient squamous cell carcinoma from transition zones.

Author information

1
Division of Developmental Biology, Cincinnati Children's Hospital Medical Center, Cincinnati, United States.
2
Centre de Recherche en Cancérologie de Marseille (CRCM), Inserm, U1068, F-13009, CNRS, UMR7258, F-13009, Institut Paoli-Calmettes, F-13009, Aix-Marseille University, UM 105, F-13284, Marseille, France.

Abstract

Squamous cell carcinomas occurring at transition zones are highly malignant tumors with poor prognosis. The identity of the cell population and the signaling pathways involved in the progression of transition zone squamous cell carcinoma are poorly understood, hence representing limited options for targeted therapies. Here, we identify a highly tumorigenic cancer stem cell population in a mouse model of transitional epithelial carcinoma and uncover a novel mechanism by which loss of TGFβ receptor II (Tgfbr2) mediates invasion and metastasis through de-repression of ELMO1, a RAC-activating guanine exchange factor, specifically in cancer stem cells of transition zone tumors. We identify ELMO1 as a novel target of TGFβ signaling and show that restoration of Tgfbr2 results in a complete block of ELMO1 in vivo. Knocking down Elmo1 impairs metastasis of carcinoma cells to the lung, thereby providing insights into the mechanisms of progression of Tgfbr2-deficient invasive transition zone squamous cell carcinoma.

KEYWORDS:

TGFbeta signaling; cancer biology; cancer stem cells; developmental biology; mouse; squamous cell carcinoma; stem cells; transition zones

PMID:
28219480
PMCID:
PMC5319840
DOI:
10.7554/eLife.22914
[Indexed for MEDLINE]
Free PMC Article

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