2. Academic Validation
  3. Mitochondrial fission links ECM mechanotransduction to metabolic redox homeostasis and metastatic chemotherapy resistance

Mitochondrial fission links ECM mechanotransduction to metabolic redox homeostasis and metastatic chemotherapy resistance

  • Nat Cell Biol. 2022 Feb;24(2):168-180. doi: 10.1038/s41556-022-00843-w.
Patrizia Romani 1,  Nunzia Nirchio 1,  Mattia Arboit 2,  Vito Barbieri 3 4,  Anna Tosi 4,  Federica Michielin 5,  Soichi Shibuya 5,  Thomas Benoist 5,  Danchen Wu 6,  Charles Colin Thomas Hindmarch 6,  Monica Giomo 7 8,  Anna Urciuolo 1 9,  Flavia Giamogante 10,  Antonella Roveri 1,  Probir Chakravarty 11,  Marco Montagner 1,  Tito Calì 10,  Nicola Elvassore 5 7 8,  Stephen L Archer 6,  Paolo De Coppi 5,  Antonio Rosato 3 4,  Graziano Martello 2,  Sirio Dupont 12
Affiliations

Affiliations

  • 1 Department of Molecular Medicine (DMM), University of Padua, Padua, Italy.
  • 2 Department of Biology (DiBio), University of Padua, Padua, Italy.
  • 3 Department of Surgery, Oncology and Gastroenterology (DiSCOG), University of Padua, Padua, Italy.
  • 4 Veneto Institute of Oncology IOV-IRCCS, Padua, Italy.
  • 5 Institute of Child Health, NIHR Biomedical Research Centre, Great Ormond Street Institute of Child Health, UCL, London, UK.
  • 6 Department of Medicine, Queen's University, Kingston, Ontario, Canada.
  • 7 Department of Industrial Engineering (DII), University of Padua, Padua, Italy.
  • 8 Venetian Institute of Molecular Medicine (VIMM), Padua, Italy.
  • 9 Fondazione Istituto di Ricerca Pediatrica (IRP), Città della Speranza, Padua, Italy.
  • 10 Department of Biomedical Sciences (DSB), University of Padua, Padua, Italy.
  • 11 Bioinformatics Platform, The Francis Crick Institute, London, UK.
  • 12 Department of Molecular Medicine (DMM), University of Padua, Padua, Italy. sirio.dupont@unipd.it.
PMID: 35165418 DOI: 10.1038/s41556-022-00843-w
Abstract

Metastatic breast Cancer cells disseminate to organs with a soft microenvironment. Whether and how the mechanical properties of the local tissue influence their response to treatment remains unclear. Here we found that a soft extracellular matrix empowers redox homeostasis. Cells cultured on a soft extracellular matrix display increased peri-mitochondrial F-actin, promoted by Spire1C and Arp2/3 nucleation factors, and increased DRP1- and MIEF1/2-dependent mitochondrial fission. Changes in mitochondrial dynamics lead to increased production of mitochondrial Reactive Oxygen Species and activate the NRF2 antioxidant transcriptional response, including increased cystine uptake and glutathione metabolism. This retrograde response endows cells with resistance to oxidative stress and reactive oxygen species-dependent chemotherapy drugs. This is relevant in a mouse model of metastatic breast Cancer cells dormant in the lung soft tissue, where inhibition of DRP1 and NRF2 restored cisplatin sensitivity and prevented disseminated cancer-cell awakening. We propose that targeting this mitochondrial dynamics- and redox-based mechanotransduction pathway could open avenues to prevent metastatic relapse.

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