BEYOND CHEMICAL SIGNALING: MECHANICAL FORCES AS DRIVERS OF MITOTIC AND METABOLIC CONTROL

Mechanotransduction, the process through which cells sense and respond to mechanical stimuli, plays a crucial role in cell homeostasis, survival and proliferation. Different types of human tissues present various mechanical properties, determinant for cell fate and health. Metabolic regulation and mitosis are among the most essential processes carried out by the cell. Although both have been extensively characterized biochemically and genetically, less is known about their mechanics and the central role played by mechanotransduction in their modulation. To elucidate these mechanisms, we deployed novel tools to exert mechanical stress on cells while monitoring their response. First, we investigated the effects of compression on cell division while targeting the DNA damage response kinase ATR. ATR mediates nuclear mechanotransduction and chromosome segregation, and its inhibition resulted in defective cell division and mitotic errors in presence of compression. Tumors are mechanically challenging microenvironments, and ATR inhibition may represent a strategy to increase tumor vulnerability. Secondly, to study the crosstalk between metabolism and mechanotransduction, we combined carbon starvation to mechanical stimulation in normal and cancer cells. Malignancy is accompanied by metabolic rearrangements, hindering the efficacy of therapies. We showed that modulation of mechanical forces and nutrient availability leads to differential responses in different cell types. Metabolic interventions could thus leverage the mechanics of a tumor as key components of therapy. Here, we developed ways to isolate the effects of mechanical stress on metabolism and cell division, confirming the importance of an integrated perspective on cell biology that includes mechanotransduction as a fundamental component.