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Activation of an actin signaling pathway in pre-malignant mammary epithelial cells by P-cadherin is essential for transformation.

Lídia FariaSara CanatoTito T JesusMargarida GonçalvesPatrícia S GuerreiroCarla S LopesIsabel MeirelesEurico Morais-de-SáJoana ParedesFlorence Janody
Published in: Disease models & mechanisms (2023)
Alterations in the expression or function of cell adhesion molecules have been implicated in all steps of tumor progression. Among those, P-cadherin is highly enriched in basal-like breast carcinomas, playing a central role in cancer cell self-renewal, collective cell migration and invasion. To establish a clinically relevant platform for functional exploration of P-cadherin effectors in vivo, we generated a humanized P-cadherin Drosophila model. We report that actin nucleators, Mrtf and Srf, are main P-cadherin effectors in fly. We validated these findings in a human mammary epithelial cell line with conditional activation of the SRC oncogene. We show that, prior to promoting malignant phenotypes, SRC induces a transient increase in P-cadherin expression, which correlates with MRTF-A accumulation, its nuclear translocation and the upregulation of SRF target genes. Moreover, knocking down P-cadherin, or preventing F-actin polymerization, impairs SRF transcriptional activity. Furthermore, blocking MRTF-A nuclear translocation hampers proliferation, self-renewal and invasion. Thus, in addition to sustaining malignant phenotypes, P-cadherin can also play a major role in the early stages of breast carcinogenesis by promoting a transient boost of MRTF-A-SRF signaling through actin regulation.
Keyphrases
  • cell migration
  • cell adhesion
  • poor prognosis
  • signaling pathway
  • stem cells
  • cell proliferation
  • pi k akt
  • long non coding rna
  • single cell
  • dna methylation
  • cerebral ischemia
  • oxidative stress
  • induced apoptosis