Contributed Talk

Surviving under pressure: mechano-metabolic regulation of cell density homeostasis

Giuseppe Fragale¹, Benjamin Hershey¹, Nicola Manfrini², Stefano Biffo², Kristina Havas¹

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Tumor onset is linked to increased local cell density, extracellular matrix deposition, and stromal cell expansion. In solid tumors, these factors create mechanical stress in and around the tumor. While this stress can cause growth arrest in healthy tissues, tumor stiffness is connected to cancer progression and metastasis. Intriguingly, it was recently demonstrated that the accumulation of solid stress leads to dysregulation of intracellular density homeostasis. It remains unknown how cells regulate their intracellular density and whether changes in cytosolic density could be beneficial for cellular fitness under certain conditions, such as during the acute mechanical stress associated with metastatic dissemination. Through the application of biophysical principles to the fields of cellular metabolism and translation, our research aims to address these questions.
We show that the application of compressive stress results in an increase in macromolecular crowding, which slowly recovers to baseline levels. Investigating the mechanisms behind this adaptation, we have unveiled a biphasic mechano-metabolic response. In the initial phase, we observe a dominant, mTORC1-independent biophysical regulation of translation. We demonstrate that solid stress induces fission of the mitochondria network, which triggers a redox imbalance leading to inhibition of translation. Subsequently, we observe an inhibition of mTORC1, which is accompanied by increased autophagy. By using TSC2kd cell lines, we demonstrate that although mTORC1 inactivation is dispensable for the initial inhibition of translation, it is absolutely required for the restoration of density homeostasis. Our project not only elucidates the adaptive strategies employed by tumors but also offers valuable insights into potential therapeutic targets for intervention.