Tissue fluidification promotes a cGAS-STING cytosolic DNA response in invasive breast cancer

Autor(en)

Emanuela Frittoli, Andrea Palamidessi, Fabio Iannelli, Federica Zanardi, Stefano Villa, Leonardo Barzaghi, Hind Abdo, Valeria Cancila, Galina V. Beznoussenko, Giulia Della Chiara, Massimiliano Pagani, Chiara Malinverno, Dipanjan Bhattacharya, Federica Pisati, Weimiao Yu, Viviana Galimberti, Giuseppina Bonizzi, Emanuele Martini, Alexander A. Mironov, Ubaldo Gioia, Flora Ascione, Qingsen Li, Kristina Havas, Serena Magni, Zeno Lavagnino, Fabrizio Andrea Pennacchio, Paolo Maiuri, Silvia Caponi, Maurizio Mattarelli, Sabata Martino, Fabrizio d'Adda di Fagagna, Chiara Rossi, Marco Lucioni, Richard Tancredi, Paolo Pedrazzoli, Andrea Vecchione, Cristiano Petrini, Francesco Ferrari, Chiara Lanzuolo, Giovanni Bertalot, Guilherme Nader, Marco Foiani, Matthieu Piel, Roberto Cerbino, Fabio Giavazzi, Claudio Tripodo, Giorgio Scita

Abstrakt

The process in which locally confined epithelial malignancies progressively evolve into invasive cancers is often promoted by unjamming, a phase transition from a solid-like to a liquid-like state, which occurs in various tissues. Whether this tissue-level mechanical transition impacts phenotypes during carcinoma progression remains unclear. Here we report that the large fluctuations in cell density that accompany unjamming result in repeated mechanical deformations of cells and nuclei. This triggers a cellular mechano-protective mechanism involving an increase in nuclear size and rigidity, heterochromatin redistribution and remodelling of the perinuclear actin architecture into actin rings. The chronic strains and stresses associated with unjamming together with the reduction of Lamin B1 levels eventually result in DNA damage and nuclear envelope ruptures, with the release of cytosolic DNA that activates a cGAS-STING (cyclic GMP-AMP synthase-signalling adaptor stimulator of interferon genes)-dependent cytosolic DNA response gene program. This mechanically driven transcriptional rewiring ultimately alters the cell state, with the emergence of malignant traits, including epithelial-to-mesenchymal plasticity phenotypes and chemoresistance in invasive breast carcinoma.

Organisation(en)

Computergestützte Physik und Physik der Weichen Materie

Externe Organisation(en)

IFOM, Italy, Università degli Studi di Milano-Bicocca, Max-Planck-Institut für Dynamik und Selbstorganisation, Università degli Studi di Palermo, Agency for Science, Technology and Research A*STAR, Istituto Europeo di Oncologia, Università degli studi di Napoli Federico II, Università degli Studi di Perugia, Consiglio Nazionale delle Ricerche, Fondazione IRCCS Policlinico San Matteo, Università degli studi di Pavia, Ospedale Uboldo, Università degli Studi di Roma La Sapienza, Ospedale Santa Chiara di Trento, Università degli Studi di Trento, Centre National De La Recherche Scientifique (CNRS), Université de recherche Paris Sciences et Lettres, Institut Curie, Istituto Nazionale Genetica Moleccolare (INGM)

Journal

Nature Materials

Band

22

Seiten

644–655

Anzahl der Seiten

12

ISSN

1476-1122

DOI

https://doi.org/10.1038/s41563-022-01431-x

Publikationsdatum

12-2022

Peer-reviewed

Ja

ÖFOS 2012

104004 Chemische Biologie, 103018 Materialphysik

Schlagwörter

ASJC Scopus Sachgebiete

Condensed Matter Physics, Mechanics of Materials, Mechanical Engineering, Allgemeine Chemie, Allgemeine Materialwissenschaften

Sustainable Development Goals

SDG 3 – Gesundheit und Wohlergehen

Link zum Portal

https://ucrisportal.univie.ac.at/de/publications/33621404-d79f-4a85-8229-dabe2a5b319c