1. Academic Validation
  2. Noncanonical Wnt signaling promotes colon tumor growth, chemoresistance and tumor fibroblast activation

Noncanonical Wnt signaling promotes colon tumor growth, chemoresistance and tumor fibroblast activation

  • EMBO Rep. 2023 Jan 27;e54895. doi: 10.15252/embr.202254895.
Guillem Fuertes # 1 2 Beatriz Del Valle-Pérez # 1 2 3 Javier Pastor 1 2 Evelyn Andrades 4 5 Raúl Peña 2 Antonio García de Herreros 2 3 Mireia Duñach 1
Affiliations

Affiliations

  • 1 Departament de Bioquímica i Biologia Molecular, CEB, Facultat de Medicina, Universitat Autònoma de Barcelona, Bellaterra, Spain.
  • 2 Programa de Recerca en Càncer, Institut Hospital del Mar d'Investigacions Mèdiques (IMIM), Unitat Associada al CSIC, Barcelona, Spain.
  • 3 Departament de Medicina i Ciències de la Vida, Universitat Pompeu Fabra, Barcelona, Spain.
  • 4 Departament de Dermatologia, Hospital del Mar, Barcelona, Spain.
  • 5 Grup de Malalties Inflamatòries i Neoplàsiques Dermatològiques, Institut Hospital del Mar d'Investigacions Mèdiques (IMIM), Barcelona, Spain.
  • # Contributed equally.
Abstract

Colon tumors of the mesenchymal subtype have the lowest overall survival. Snail1 is essential for the acquisition of this phenotype, characterized by increased tumor stemness and invasion, and high resistance to chemotherapy. Here, we find that Snail1 expression in colon tumor cells is dependent on an autocrine noncanonical Wnt pathway. Accordingly, depletion of Ror2, the co-receptor for noncanonical Wnts such as Wnt5a, potently decreases Snail1 expression. Wnt5a, Ror2, and Snail1 participate in a self-stimulatory feedback loop since Wnt5a increases its own synthesis in a Ror2- and Snail1-dependent fashion. This Wnt5a/Ror2/Snail1 axis controls tumor invasion, chemoresistance, and formation of tumor spheres. It also stimulates TGFβ synthesis; consequently, tumor cells expressing Snail1 are more efficient in activating cancer-associated fibroblasts than the corresponding controls. Ror2 downmodulation or inhibition of the Wnt5a pathway decreases Snail1 expression in primary colon tumor cells and their ability to form tumors and liver metastases. Finally, the expression of SNAI1, ROR2, and WNT5A correlates in human colon and other tumors. These results identify inhibition of the noncanonical Wnt pathway as a putative colon tumor therapy.

Keywords

Snail1; cancer stem cell; chemoresistance; metastasis; noncanonical Wnt.

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