MechanoSecret · Exploring the Mechanobiology of the Secretory pathway across scales

Membrane trafficking is fundamental to cellular homeostasis, controlling essential processes ranging from signalling to adaptation to the environment. By regulating secretion, eukaryotic cells modulate plasma membrane composition and the extracellular matrix. Human cells are typically embedded in tissues and constantly experience external forces. While the molecular details of the secretory pathway are well-established in 2D cultures, their response to mechanical cues remains largely unexplored.This project aims to fill this knowledge gap by investigating how the Golgi complex, the central hub of the secretory pathway, responds to external mechanical forces. Using cutting-edge microscopy, biomaterials, and advanced cell biology, our study will adopt a bottom-up approach. First, we will explore the fundamental biology of the secretory pathway mechanotransduction in 2D polarized and non-polarized cells. Employing super-resolution microscopy and single-particle tracking, we will analyse how external mechanical forces influence Golgi dynamics with unprecedented spatiotemporal resolution. Our second aim extends this research to 3D systems, hypothesizing that inherent forces in these environments affect the secretory pathway. By leveraging colorectal cancer patient-derived organoids, we aim to uncover changes in secretion under mechanostimulation. This project will pioneer single-particle tracking in 3D imaging, integrating expertise from cell biology, optics, and photonics—a synergy uniquely supported by the host institution.Colorectal cancer, a prevalent and deadly malignancy, suffers from limited therapeutic options due to cellular heterogeneity. By bridging cell biology and biophysics with cancer research, this project holds the potential to identify novel vulnerabilities in colorectal cancer. This study will not only provide fundamental insights into the secretory pathway but also lay the groundwork for future therapeutic strategies against colorectal cancer.