How tumour cells hijack apical extrusion and how they can be targeted

Abstract

Tissue development and cell behavior are influenced not only by chemical signals but also by physical ones. The responses of cells to mechanical forces can range from the immediate adjustment of cell morphology and motility to long-term genome reorganisation and cell fate changes. Mechanotransduction plays a vital role in development and tissue homeostasis, influencing cell proliferation, differentiation, and migration. Disruptions to these forces or inadequate cellular responses may result in developmental anomalies and diseases, including atherosclerosis and cancer. Cancer cells exhibit perturbed force transmission compared to normal tissue due to alterations in the force-sensing network and the downregulation of membrane molecules and cytoskeleton components. These alterations enable cancer cells to overcome mechanical constraints, proliferate, and expand spontaneously. Angiomotin-like 2 (AmotL2) has been found to play crucial roles in connecting and regulating force transmission, maintaining cell geometry, and cell polarity. The shorter isoform, p60AmotL2, has been associated with poor progression in cancer patients. This thesis builds on earlier research to gain a more thorough understanding of the functional processes and potential therapeutics related to the p60 isoform of AmotL2.

We initially discovered that p60AmotL2 acts as a molecular clutch, disengaging the Ecadherin/ p100AmotL2/actin-LINC complex and thereby affecting mechanotransduction from neighbouring cells. This disrupts the structural integrity of the nucleus and increases the cells' invasive capacity. Following these findings, we investigated the potential role of p60AmotL2 in normal epithelial physiological processes. The results revealed a correlation between p60AmotL2 and cell extrusion, a key process in epithelial homeostasis. The findings indicate that p60AmotL2 expression triggers neighbouring cells to initiate live-cell apical extrusion. Since cell extrusion is a mechanism by which the epithelium removes altered cells and prevents tumour growth, these findings underscore the tumourigenic characteristics of p60AmotL2.

Given the tumour-promoting properties of p60AmotL2, as demonstrated in earlier studies, our research aimed to develop a pharmacological screening technique to discover promising compounds that target cells expressing p60AmotL2. The findings revealed that BET inhibitors (BETi) are more effective on p60AmotL2-expressing cells in three-dimensional cultures. The data also suggest that p60AmotL2 may be a potential therapeutic target to prevent tumour invasion.