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

Heather A Mccauley,Géraldine Guasch,Véronique Chevrier,Daniel Birnbaum

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.

Highlights

Transition zones are distinct anatomical regions between two different types of epithelia, and function as stem cell niches in many regions of the body (Runck et al, 2010; San Roman et al, 2011; Mcnairn and Guasch, 2011)
We used the murine Tgfbr2-deficient anorectal squamous cell carcinoma (SCC) model to study the consequences of loss of transforming growth factor beta” (TGFb) signaling in cancer stem cells (CSCs)-driven tumor propagation and metastasis. We found that these Tgfbr2 cKO anorectal SCC, which spontaneously metastasize to the lungs, contain a unique population of epithelial cells with features of CSCs, including: expression of the CSC marker CD34, clonogenicity in vitro, tumorigenicity in vivo, and upregulation of genes associated with invasion and metastasis
To lineage trace Tgfbr2-deficient cells within these transitional SCC and enable isolation of specific Tgfbr2-deficient tumor cell populations, we backcrossed these mice into mice containing loxP sites flanking a STOP sequence preceding Enhanced Yellow Fluorescent Protein gene (eYFP) inserted into the Rosa26 locus (Figure 1—figure supplement 1), such that all Keratin 14 (K14)-positive epithelial cells, including the anorectal SCC cells, while conditionally null for Tgfbr2 expressed YFP

Summary

Introduction

Transition zones are distinct anatomical regions between two different types of epithelia, and function as stem cell niches in many regions of the body (Runck et al, 2010; San Roman et al, 2011; Mcnairn and Guasch, 2011). Transition zones are uniquely susceptible to carcinogenesis, and the resulting tumors are typically highly malignant and associated with poor prognosis (San Roman et al, 2011; Mcnairn and Guasch, 2011; Flesken-Nikitin et al, 2013; Grodsky, 1961). Cervical cancers arise at the transition between the columnar epithelium of the endocervix and the squamous epithelium of the ectocervix

Methods

Results

Conclusion