Deciphering E-cadherin secretion leads the way to anti-metastatic drugs

Cadherins are cell surface glycoproteins with important functions in cell-cell adhesion, tissue pattering and cancer. E-cadherin is a key component of the apical zonula adherens in epithelial monolayers, and is considered a master regulator of the epithelial phenotype, due in part to the association of the zonula adherens with a sub-membrane acto-myosin circumferential ring, which stabilizes the epithelial architecture. Moreover, E-cadherin guarantees epithelial integrity by providing cell-cell adhesion. For example, in cancer, loss of E-cadherin is associated with the transition from a more differentiated phenotype to a more motile, invasive and aggressive phenotype. E-cadherin has been proposed as a tumor suppressor gene and by in vitro and in vivo models the loss of E-cadherin-mediated cell–cell adhesion in cancer cells was proven to be the cause of the acquisition of mesenchymal features, thus leading to metastasis formation. These processes appear very similar to those occurring during tissue development, leading to the epithelial–mesenchymal transition. The emerging role of E-cadherin participating in cancer-associated signaling surely justifies the recent efforts to possibly design a therapeutic approach able to promote E-cadherin function in tumours. For instance, the development of a compound that promotes the presence of E-cadherin at the cell surface would stimulate tumour cell cohesion and thus counteract metastasis. Such an anti-cancer drug would be directed against large subsets of progressive cancers.

Given their constant renewal and exposure to mechanical stress, epithelial tissues require a high level of flexibility. The exchange of E-cadherin molecules at the plasma membrane, which is made possible by the movement of membrane vesicles, is essential for plasticity. E-cadherin distribution at the plasma membrane alters during epithelial-mesenchymal transitions (EMT), which are a driving factor in embryonic development and permit cell migration.
Many disorders, including cancer, where the loss of E-cadherin mediated cell-cell adhesion is an important step during metastasis, are caused by defects in E-cadherin trafficking. Because it promotes cell-cell adhesion, E-cadherin plays a crucial role in epithelial tissues. Cell polarity and epithelial homeostasis depend on polarised E-cadherin exocytosis to the lateral plasma membrane. A requirement for metastasis, loss of E-cadherin secretion affects tissue integrity. Although E-cadherin secretion plays a crucial role, the transport mechanism is still a mystery.

In a new research study published in the journal Traffic, German researchers at Heidelberg University, Dajana Tanasic, Nicola Berns, and led by Dr. Veit Riechmann recently demonstrated that Myosin V facilitates polarized E-cadherin secretion and identified two distinct transport pathways to the plasma membrane: first, a crucial actin channel that directs E-cadherin vesicles to the zonula adherens, and second, parallel actin packets in the basal epithelium that direct E-cadherin. Additionally, they demonstrate that apical endosomes serve as sorting hubs for polarized E-cadherin secretion, where Rab7 and Snx16 collaborate to transport E-cadherin into the Rab11 compartments. The research was performed in the follicular epithelium of Drosophila, which serves a good model for E-cadherin trafficking due to diverse genetic tools and low gene redundancy.

The research team showed that E-cadherin is conveyed to endosomes that are located in the apical portion of the epithelium after being endocytosed from the lateral plasma membrane. The transfer of freshly translated E-cadherin to these apical endosomes converges the biosynthetic and recycling routes. The authors showed that Snx16, which Rab7 attracts to these endosomes, tubulates E-cadherin into the Rab11 domain. By enlisting Sec15 and MyoV as its effectors, Rab11 directs the production of E-cadherin transport vesicles. A different channel secretes DE-cadherin to the lateral PM, where punctate adherens connections form. Their studies pinpoint to this channel to the epithelium’s basal-most area, where parallel actin bundles serve as a pathway for the MyoV/E-cadherin vesicles. Further investigations revealed that Sec15 also co-localizes with Rab11 and MyoV in the basal region, indicating that the basal vesicles also need the exocyst complex to fuse with the PM. Snx16 moves E-cadherin from the Rab7 into the Rab11 compartment in order to recycle it. According to the authors Snx16 and Rab7 are necessary for effective DE-cadherin sorting in endosomes; however, mutant cells exhibit minor deficiencies, suggesting that DE-cadherin secretion is not entirely eliminated. Therefore the new research sheds fresh light on how DE-cadherin is sorted within endosomes, although numerous molecular pathways remain to be understood.

In conclusion, the new elaborate model identified by Dr. Veit Riechmann and his colleagues for DE-cadherin trafficking in the follicular epithelium offers a suitable framework to comprehend how deficient trafficking starts disease processes. The identification of Rab7, Snx16 and Myosin V as proteins facilitating E-cadherin secretion makes it possible to search for compounts that help these proteins to promote E-cadherin secretion in such disease processes. In this context, Snx16 will be particularly interesting because it has already been shown that Snx16 overexpression counteracts cell migration and tumorigenesis in cancer cell lines. Agents enhancing Snx16 activity could therefore stimulate E-cadherin secretion and prevent tumour metastasis. These findings thus enhance our knowledge of how polarised E-cadherin secretion preserves the epithelial architecture and inhibits metastasis and hopefully will assist in designing advanced E-cadherin antitumor drugs.