Abstract
Loss of the desmosomal cell–cell adhesion molecule, Desmoglein 1 (Dsg1), has been reported as an indicator of poor prognosis in head and neck squamous cell carcinomas (HNSCC) overexpressing epidermal growth factor receptor (EGFR). It has been well established that EGFR signaling promotes the formation of invadopodia, actin-based protrusions formed by cancer cells to facilitate invasion and metastasis, by activating pathways leading to actin polymerization and ultimately matrix degradation. We previously showed that Dsg1 downregulates EGFR/Erk signaling by interacting with the ErbB2-binding protein Erbin (ErbB2 Interacting Protein) to promote keratinocyte differentiation. Here, we provide evidence that restoring Dsg1 expression in cells derived from HNSCC suppresses invasion by decreasing the number of invadopodia and matrix degradation. Moreover, Dsg1 requires Erbin to downregulate EGFR/Erk signaling and to fully suppress invadopodia formation. Our findings indicate a novel role for Dsg1 in the regulation of invadopodia signaling and provide potential new targets for development of therapies to prevent invadopodia formation and therefore cancer invasion and metastasis.
| Original language | English (US) |
|---|---|
| Pages (from-to) | 1195-1206 |
| Number of pages | 12 |
| Journal | Molecular Cancer Research |
| Volume | 17 |
| Issue number | 5 |
| DOIs | |
| State | Published - May 2019 |
Funding
The authors would like to thank Jennifer L. Koetsier for optimization of experiments, Bethany Perez-White for her helpful advice on the spheroid invasion assay, and all the members of the Green laboratory for insightful discussions during development of this project. Gifts were provided by Sharon Stack (Cal33 cell line), Jennifer Grandis (SCC25 cell line), J. Rheinwald (SCC9 cell line), Thomas Carey (SCC22B and UMSCC1 cell lines), M. Takeichi and O. Abe (E-cadherin antibody), Julie Segre (K5 and K1 antibodies), and G. Nolan (Phoenix package cell line). NHEK cells were obtained from the Keratinocyte Core of the Northwestern University Skin Disease Research Center. This work was supported by NIH grants R01 CA122151, R01 AR041836, and R37 AR043380 with partial support from the J.L. Mayberry Endowment to K.J. Green. A. Valenzuela-Iglesias was supported by a Postdoctoral Fellowship Grant by the Consejo Nacional de Ciencia y Tecnología, CONACYT, Mexico.
ASJC Scopus subject areas
- Molecular Biology
- Oncology
- Cancer Research
