SURVIVING UNDER PRESSURE: TRANSLATIONAL REWIRING IN RESPONSE TO MECHANICAL STIMULI

An outcome of high mechanical stress in the context of hyperproliferation and increased cellular tension is the reduction in cell volume, that holds the potential to impact cellular density. Both cell size and density homeostasis are integral features of healthy tissues, intricately linked to the regulation of the cell cycle and biosynthesis processes. This connection suggested that achieving density homeostasis could involve a coupling mechanism between the regulation of macromolecular production and osmolytes. Considering the importance of density and protein homeostasis, we decided to explore whether similar mechanisms may play a role in the responses of tumor cells upon mechanical stress. To shed light on the mechanisms, we have employed several approaches to study the acute alterations in cell size induced by mechanical stress. We used osmotic shocks and compressive stresses, as well as genetic encoded microparticle (GEMs) tracking to infer cytoplasmic density. The combination of these tools with measures of translation rate, polysome profiling, ribogenesis, and protein degradation assays uncovered interesting evidences demonstrating a mechanism that couples the regulation of macromolecular production with rheological adaptation in colorectal cancer cells HCT116. In particular, we have found that the early response to mechanical compression is independent of the mechanistic target of rapamycin complex 1 (mTORC1), while adaptation requires mTORC1 inactivation and subsequent increase of autophagy. Our data provided clues suggesting alternative signaling and biophysical pathways involved in the regulation of protein homeostasis in response to mechanical stress, which provide valuable insights into the pathogenesis of cancer and may represent promising targets for therapeutic intervention.

Grantor dc:publisher

Università degli Studi di Milano

Year dc:date

2024

Author dc:creator

• FRAGALE, GIUSEPPE

Contributors dc:contributor

• tutor: K. Havas ; co-tutor: M. Foiani
• Delarue
• Morgan
• G. Fragale

• Settore BIO/10 - Biochimica

Statement dc:rights

• info:eu-repo/semantics/openAccess

Language dc:language

eng

Identifier

http://dx.doi.org/10.13130/fragale-giuseppe_phd2024-04-11
10.13130/fragale-giuseppe_phd2024-04-11

OAI identifier oai:identifier

oai:air.unimi.it:2434/1040539