Special Colloquium
Using cellular phase transitions to understand cancer
Speaker: Roberto Cerbino (Faculty of Physics, University of Vienna, Vienna, Austria)
Abstract: Cells in groups can exhibit a variety of emergent and collective behaviors that differ from those observed in isolated cells. A key aspect of these behaviors is represented by dynamic phase transitions, which play a crucial role in both physiological and pathological processes that alter the tissue’s biophysical state. Two particularly notable transitions relevant for epithelial cells are cellular jamming and unjamming. The jamming transition leads to tissue rigidity characteristic of a mature tissue, while the reverse unjamming transition imparts a viscoelastic, liquid-like state to otherwise solid-like epithelia.
We have recently discovered that the small GTPase RAB5a is one of the few known molecular drivers of the unjamming transition. Its elevated expression triggers a dramatic transition in 2D monolayers, characterized by flocking, and in 3D spheroids, evidenced by coherent rotations. This transition is associated with a general decrease in cell surface tension and an increased ability for individual cells to align their self-propulsion force with neighboring cells. Notably, RAB5a is overexpressed in particularly aggressive mammary tumors. This phenomenon is likely related to the ability of unjammed spheroids to exert sufficient forces on the extracellular matrix, eventually degrading it and leading to an in vitro equivalent of invasion and metastasis. Furthermore, the unjammed state is characterized by giant density fluctuations that subject the nuclei to prolonged nuclear mechanical stress, ultimately causing the nuclear membrane to break and nuclear DNA to extravasate into the cytoplasm. This cytosolic DNA can activate the cGAS-STING pathway, a central component of the innate immune system, which can play both tumor-suppressive and tumor-promoting roles, with the specific role in our system yet to be fully understood.
Our results underline the significance of tissue biophysical properties in understanding tumor progression dynamics. They also suggest that a combination of mechanical and pharmacological interventions might offer new avenues to interfere with tumor development.
