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

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

doi:10.1038/s41563-022-01431-x

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

Emanuela Frittoli
, Andrea Palamidessi (Corresponding author)
, 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 (Corresponding author), Claudio Tripodo (Corresponding author), Giorgio Scita (Corresponding author)

Computational and Soft Matter Physics

Publications: Contribution to journal › Article › Peer Reviewed

Abstract

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.

Original language	English
Pages (from-to)	644–655
Number of pages	12
Journal	Nature Materials
Volume	22
Issue number	5
Early online date	29 Dec 2022
DOIs	https://doi.org/10.1038/s41563-022-01431-x
Publication status	Published - May 2023

Funding

We thank M. Riboni, S. Minardi, V.Dall'Olio and L. Tizzoni at Cogentech for gene expression profiling and qRT-PCR services; D.Parazzoli, S.Barozzi and the imaging unit of IFOM cell culture facility for technical assistance; F. Pramotton, A. Poli and the cleanroom facilities of the Binning and Rohrer Nanotechnology Center for assistance with the microchannel apparatus. Thank you to the Biobankl for Translational and Digital Medicine Unit (B4MED) of the European Institute of Oncology for support in providing breast cancer samples. This work was supported by ERC-Synergy (101071470-SHAPINCELLFATE) to G.S.; Associazione Italiana per la Ricerca sul Cancro (AIRC IG#18621 and 5Xmille#22759 to G.S., M.F. and C.T.; AIRC-IG-#21416 to M.F.; MyFirstAIRCgrant MFAG#22083 to F.G. and S.V.; AIRC-IG #21762 and AIRC 5x1000#21091 to F.d.F); the Italian Ministry of University and Scientific Research (PRIN 2017, 2017HWTP2K to G.S.; PRIN-2015SJLMB9 to M.F. and F.d.F.); the European Research Council (ERC advanced grant#835103 to F.d.F.); Progetto AriSLA 2021 'DDR & ALS; FRRB-Fondazione Regionale per la Ricerca Biomedica-under the frame of EJP RD, the European Joint Programme on Rare Diseases with funding from the European Union's Horizon 2020 research and innovation programme under the EJP RD COFUND-EJP No 825575 to F.g.F.; from LABEX DCBIOL (ANR-10-IDEX-0001-02 PSL* and ANR-11-LABX-0043), ANR ANR-17-CE15-0025-01 and ANR-18-CE92-0022-01, INSERM 19CS007-00, INCA PLBIO to N.M.; and INCA PLBIO 2019-1-PL BIO-07-ICR-1, INSERM Plan Cancer Single Cell grant 19CS007-00 to M.P.. H.A. is supported by a fellowship from Fondazione Umberto Veronesi; L.B. is supported by a fellowship from the Associazione Italiana per la Ricerca sul Cancro.

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

SDG 3 Good Health and Well-being

Austrian Fields of Science 2012

104004 Chemical biology
103018 Materials physics

Keywords

EPITHELIAL-MESENCHYMAL TRANSITION
GMP-AMP SYNTHASE
COMET ASSAY
IN-SITU
INNATE
DAMAGE
IMAGE
METASTASIS
MICROSCOPY
MIGRATION

Access to Document

10.1038/s41563-022-01431-xLicence: CC BY 4.0

Cite this

Frittoli, E., Palamidessi, A., Iannelli, F., Zanardi, F., Villa, S., Barzaghi, L., Abdo, H., Cancila, V., Beznoussenko, G. V., Della Chiara, G., Pagani, M., Malinverno, C., Bhattacharya, D., Pisati, F., Yu, W., Galimberti, V., Bonizzi, G., Martini, E., Mironov, A. A., ... Scita, G. (2023). Tissue fluidification promotes a cGAS-STING cytosolic DNA response in invasive breast cancer. Nature Materials, 22(5), 644–655. https://doi.org/10.1038/s41563-022-01431-x

@article{33621404d79f4a858229dabe2a5b319c,

title = "Tissue fluidification promotes a cGAS-STING cytosolic DNA response in invasive breast cancer",

abstract = "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.",

keywords = "EPITHELIAL-MESENCHYMAL TRANSITION, GMP-AMP SYNTHASE, COMET ASSAY, IN-SITU, INNATE, DAMAGE, IMAGE, METASTASIS, MICROSCOPY, MIGRATION",

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

note = "Publisher Copyright: {\textcopyright} 2022, The Author(s).",

year = "2023",

month = may,

doi = "10.1038/s41563-022-01431-x",

language = "English",

volume = "22",

pages = "644{\textendash}655",

journal = "Nature Materials",

issn = "1476-1122",

publisher = "NATURE PUBLISHING GROUP",

number = "5",

}

Frittoli, E, Palamidessi, A, Iannelli, F, Zanardi, F, Villa, S, Barzaghi, L, Abdo, H, Cancila, V, Beznoussenko, GV, Della Chiara, G, Pagani, M, Malinverno, C, Bhattacharya, D, Pisati, F, Yu, W, Galimberti, V, Bonizzi, G, Martini, E, Mironov, AA, Gioia, U, Ascione, F, Li, Q, Havas, K, Magni, S, Lavagnino, Z, Pennacchio, FA, Maiuri, P, Caponi, S, Mattarelli, M, Martino, S, di Fagagna, FDA, Rossi, C, Lucioni, M, Tancredi, R, Pedrazzoli, P, Vecchione, A, Petrini, C, Ferrari, F, Lanzuolo, C, Bertalot, G, Nader, G, Foiani, M, Piel, M, Cerbino, R, Giavazzi, F, Tripodo, C & Scita, G 2023, 'Tissue fluidification promotes a cGAS-STING cytosolic DNA response in invasive breast cancer', Nature Materials, vol. 22, no. 5, pp. 644–655. https://doi.org/10.1038/s41563-022-01431-x

TY - JOUR

T1 - Tissue fluidification promotes a cGAS-STING cytosolic DNA response in invasive breast cancer

AU - Frittoli, Emanuela

AU - Palamidessi, Andrea

AU - Iannelli, Fabio

AU - Zanardi, Federica

AU - Villa, Stefano

AU - Barzaghi, Leonardo

AU - Abdo, Hind

AU - Cancila, Valeria

AU - Beznoussenko, Galina V.

AU - Della Chiara, Giulia

AU - Pagani, Massimiliano

AU - Malinverno, Chiara

AU - Bhattacharya, Dipanjan

AU - Pisati, Federica

AU - Yu, Weimiao

AU - Galimberti, Viviana

AU - Bonizzi, Giuseppina

AU - Martini, Emanuele

AU - Mironov, Alexander A.

AU - Gioia, Ubaldo

AU - Ascione, Flora

AU - Li, Qingsen

AU - Havas, Kristina

AU - Magni, Serena

AU - Lavagnino, Zeno

AU - Pennacchio, Fabrizio Andrea

AU - Maiuri, Paolo

AU - Caponi, Silvia

AU - Mattarelli, Maurizio

AU - Martino, Sabata

AU - di Fagagna, Fabrizio d'Adda

AU - Rossi, Chiara

AU - Lucioni, Marco

AU - Tancredi, Richard

AU - Pedrazzoli, Paolo

AU - Vecchione, Andrea

AU - Petrini, Cristiano

AU - Ferrari, Francesco

AU - Lanzuolo, Chiara

AU - Bertalot, Giovanni

AU - Nader, Guilherme

AU - Foiani, Marco

AU - Piel, Matthieu

AU - Cerbino, Roberto

AU - Giavazzi, Fabio

AU - Tripodo, Claudio

AU - Scita, Giorgio

PY - 2023/5

Y1 - 2023/5

N2 - 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.

AB - 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.

KW - EPITHELIAL-MESENCHYMAL TRANSITION

KW - GMP-AMP SYNTHASE

KW - COMET ASSAY

KW - IN-SITU

KW - INNATE

KW - DAMAGE

KW - IMAGE

KW - METASTASIS

KW - MICROSCOPY

KW - MIGRATION

UR - https://www.scopus.com/pages/publications/85145031421

U2 - 10.1038/s41563-022-01431-x

DO - 10.1038/s41563-022-01431-x

M3 - Article

SN - 1476-1122

VL - 22

SP - 644

EP - 655

JO - Nature Materials

JF - Nature Materials

IS - 5

ER -

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

Abstract

Funding

UN SDGs

Austrian Fields of Science 2012

Keywords

Access to Document

Other files and links

Fingerprint

Endocytic-mediated Tissue Fluidification in the Progression of Breast Carcinoma

Cite this

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

Abstract

Funding

UN SDGs

Austrian Fields of Science 2012

Keywords

Access to Document

Other files and links

Fingerprint

Activities

Endocytic-mediated Tissue Fluidification in the Progression of Breast Carcinoma

Cite this