Year: 2026
Type: preprint
Abstract: Compressive stress is a pervasive feature of solid tumour growth, and mechanical loading is known to activate calcium signalling through the mechanosensitive channel Piezo1. How this signal is converted into changes in cellular biosynthetic capacity, however, remains unclear. Here we show that compressive stress engages a Piezo1-dependent calcium checkpoint that reduces translational output with increasing mechanical load, independently of mTORC1 and the integrated stress response. Compression triggers Piezo1-dependent release of endoplasmic reticulum Ca²⁺, activating eEF2 kinase to slow translational elongation. This same Ca²⁺ signal drives mitochondrial remodelling and reactive oxygen species production, which reinforce translational repression through redox-dependent oxidation of the translation initiation factor eIF2β. In parallel, Ca²⁺-dependent AMPK activation triggers autophagic ribosome degradation, alleviating compression-induced macromolecular crowding and restoring cytoplasmic rheology despite sustained mechanical load. These mechanisms act at distinct levels of translational control: initiation, elongation and ribosome abundance; yet converge to limit biosynthetic output under compression. Consistent with a role for this pathway in tumour adaptation to mechanical constraint, eEF2K expression correlates with poor overall survival in a public PDAC patient dataset. Together, these findings define a mechano-metabolic checkpoint through which cells actively tune biosynthetic capacity to their physical environment.
Authors: Giuseppe Fragale, Benjamin J. Hershey, Yuwei Li, Giorgia Parodi, Galina V. Beznoussenko, Elisa Allievi, Arta Ajazi, Nicol Berti, Wanxin Zheng, Zeno Lavagnino, Vittoria Matafora, Federica Pisati, Nicola Manfrini, Stefano Biffo, Ligia Martinez, Andromachi Karakatsani, Martina Guadagno, Andreas E. Moor, Dario Parazzoli, Marco Cosentino-Lagomarsino, Davide Mazza, Angela Bachi, Paolo Maiuri, Kristina M. Havas
Institutions: IFOM, ETH Zurich, Cogentech S.R.L. Società Benefit a Socio Unico soggetta all’attività di direzione e coordinamento di IFOM - Istituto Fondazione di Oncologia Molecolare ETS (Italy), University of Milan, Istituto Nazionale Genetica Molecolare, Istituto Nazionale di Fisica Nucleare, Istituto Nazionale di Fisica Nucleare, Sezione di Milano, Vita-Salute San Raffaele University, IRCCS Ospedale San Raffaele, University of Naples Federico II, Istituto di Genetica Molecolare, National Research Council
Language: English
Subfield: Cell Biology
Domain: Life Sciences
Open Access status: green
OpenAlex ID: W7221127471