Resumen de L'eix de senyalització ror2/snail1 controla la formació de tumors colorrectals i la quimioresistència
Snail1 transcriptional factor is a key driver of EMT and controls invasion and chemo-resistance of cancer cells. Snail1 expression in tumor cells has been associated to a poor prognosis and increased resistance to chemotherapy. The exactly regulation of Snail1 in tumor cells has not been identified although several extracellular factors can induce Snail1 expression in different tumor cells and fibroblasts, such as TGF-β or Wnt factors. Canonical and non-canonical Wnt pathways are activated by Wnt factors, that can be differentiated between canonical and non-canonical Wnts. Both use a common receptor, Fz, but differ in the co-receptor, LRP5/6 for the canonical and Ror2 in the non-canonical. Both pathways also us common downstream effectors, such as Dvl2 or Fyn, although the final response is totally different. While canonical pathway promotes the stabilization of β-catenin, non-canonical Wnts promote its degradation. However, previous results of our lab have demonstrated that both, canonical and non-canonical Wnt pathways regulate a common subset of genes associated to EMT, including Snail1. In this work we have found that non-canonical Wnt pathway, and not TGF- β, is regulating Snail1 expression in colon tumor cells. Accordingly, Ror2 knock-down decreases Snail1 expression, reducing transcription and protein stability. Ror2 and Snail1 participate in a positive feedback loop, since Ror2 depletion decreases Wnt5a production. By itself, Wnt5a induces the expression of Wnt5a, Ror2, Snail1and Fz2. This Ror2/Snail1 autoactivation loop controls invasion, tumor growth and chemoresistance to cisplatin. Inhibition of Wnt5a signaling with Porcupine inhibitors decreases Snail1, Ror2 and Wnt5a expression and reduces the resistance to cisplatin in Snail1-expressing cells. Together, these results described that Snail1 expression in colon tumor cells is controlled by an autoactivated non-canonical Wnt signaling that also controls invasion and chemoresistance. Thus, inhibitors of this pathway may be useful to prevent colon tumor progression, metastasis and chemoresistance.
