Snail1 expression is required for sarcomagenesis

Abstract

Includes supplementary materials for the online appendix.

Snail1 transcriptional repressor is a major inducer of epithelial-to mesenchymal transition but is very limitedly expressed in adult animals. We have previously demonstrated that Snail1 is required for the maintenance of mesenchymal stem cells (MSCs), preventing their premature differentiation. Now, we show that Snail1 controls the tumorigenic properties of mesenchymal cells. Increased Snail1 expression provides tumorigenic capabilities to fibroblastic cells; on the contrary, Snail1 depletion decreases tumor growth. Genetic depletion of Snail1 in MSCs that are deficient in p53 tumor suppressor downregulates MSC markers and prevents the capability of these cells to originate sarcomas in immunodeficient SCID mice. Notably, an analysis of human sarcomas shows that, contrarily to epithelial tumors, these neoplasms display high Snail1 expression. This is particularly clear for undifferentiated tumors, which are associated with poor outcome. Together, our results indicate a role for Snail1 in the generation of sarcomas.

This study was funded by grants awarded by la Fundación Científica de la Asociación Española contra el Cáncer (to A.G.H., J.I.C., and F.B.), Fundación Sandra Ibarra and Ministerio de Ciencia y Tecnología (SAF2010-16089) to A.G.H. and also by RD12/0036/0005, part of “Plan Nacional de I+D+I” and cofunded by “Intituto de Salud Carlos III (ISCIII)-Subdirección General de Evaluación and Fondo Europeo de Desarrollo Regional (FEDER)”. We also acknowledge support from Fundació La Marató de TV3 (120130), to A.G.H., ISCIII/FEDER (RD12/0036/041, RD12/0036/051, and RD12/0036/021), Generalitat de Catalunya (2009SGR867 and 2009SGR321; Xarxa de Bancs de Tumors), CAM (CAM S2010-BMD2344-Colomics2), and Fundació Cellex (Barcelona). R.B. and L.A.-C. were recipients from “Formación de Personal Investigador” predoctoral fellowships.