Informace o projektu
Úloha Trop-2/Desmogleinu-2 a extracelulární matrix v regulaci invazivního chování nádorových buněk

Cancer, one of the most common diseases worldwide, is shaped by subtle differences in its malignant behaviour. These differences ultimately govern the severity of the disease and influence the ability of tumor cells to invade and establish metastases in distant organs. In tumors arising from epithelial tissues, this is often driven by epithelial-mesenchymal transition (EMT), a process that induces a phenotypic shift toward a more mesenchymal state. Notably, a frequent loss of specific intercellular adhesion molecules is observed, with the transmembrane glycoproteins Trop-2 and desmoglein-2 (DSG2) emerging as potential interacting partners whose deregulation may contribute to malignancy by weakening epithelial integrity. Nonetheless, to progress further, tumor cells must overcome the physical barrier of the basement membrane, composed of extracellular matrix (ECM) components, such as collagen IV and fibronectin. This is achieved through the expression of matrix-degrading enzymes, with matrix metalloproteinase 14 (MMP-14) playing a central role.

This work aims to elucidate how the Trop-2/DSG2 axis and the ECM regulate MMP-14-mediated matrix degradation and tumor cell invasiveness. The findings will provide new insight into the role of Trop-2, which is widely regarded as pro-metastatic and serves as the therapeutic target of the antibody-drug conjugate sacituzumab govitecan, although its full therapeutic potential remains to be defined. In our previous studies, we demonstrated that EMT negatively affects Trop-2 expression in multiple breast cancer models. Intriguingly, we also showed that Trop-2 loss leads to dysregulation of DSG2, a key desmosomal component identified as a Trop-2 interaction partner in our interactome analyses. Moreover, depletion of either Trop-2 or DSG2 was associated with increased MMP-14 expression and enhanced lung colonization by T-47D and 4T1 breast cancer cells in mouse models. However, the mechanistic understanding linking the loss of Trop-2/DSG2 to increased MMP-14 expression and invasiveness is currently lacking. This work will extend our previous findings to additional breast cancer models and provide a detailed characterization of their invasive potential in a controlled in vitro setting.