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

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

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.

MeSH terms

  • Adaptor Proteins, Signal Transducing / metabolism*
  • Animals
  • Carcinoma, Squamous Cell / physiopathology*
  • Cell Movement*
  • Disease Models, Animal
  • Gene Expression Regulation, Neoplastic*
  • Mice
  • Neoplasm Metastasis
  • Neoplastic Stem Cells / physiology*
  • Protein-Serine-Threonine Kinases / deficiency*
  • Receptor, Transforming Growth Factor-beta Type II
  • Receptors, Transforming Growth Factor beta / deficiency*

Substances

  • Adaptor Proteins, Signal Transducing
  • ELMO1 protein, mouse
  • Receptors, Transforming Growth Factor beta
  • Protein-Serine-Threonine Kinases
  • Receptor, Transforming Growth Factor-beta Type II