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Epithelial cells form tightly connected layers that function as selective barriers between internal and external environments. Beyond protection, epithelia fulfill essential physiological roles, such as nutrient absorption in the intestinal tract.

To coordinate these functions, epithelial cells need to constantly communicate, integrating not only biochemical but also mechanical signals from their surroundings. These physical cues are detected by the cell through mechanosensors, which transduce mechanical stimuli into intracellular biochemical responses. This thesis aims to advance our understanding of how epithelial cells interpret mechanical cues and translate them into changes in cell behavior, both in homeostasis and disease. Using experimental systems that allow controlled mechanical perturbation, we demonstrate that tensile forces applied to epithelial cells activate the EGFR/ERK pathway via E-cadherin–based adhesion complexes. This occurs through force-dependent activation of the protease ADAM17, which regulates the release of EGFR ligands. We further dissect the interplay between distinct mechanosensors, and show that E-cadherin and mechanosensitive ion channels establish overlapping as well as specific force-responsive signalling. Furthermore, we discuss how mechanical forces contribute to shaping the 3D architecture of the intestinal epithelium and modulate cellular responses during tissue maintenance and regeneration. Finally, we show the contribution of force-dependent mechanisms to the regulation of the intestine during tumor development. Upon invading collagen-rich stromal environments, tumor cells undergo force-dependent cellular reprogramming. This transition is governed by mechanical interactions with the extracellular matrix, mediated by integrins and mechanosensitive ion channels, and is associated with metastasis formation. Together, these findings highlight the interplay between mechanosensors in shaping epithelial cell behavior in response to different types of mechanical signals during tissue homeostasis and cancer.