Mitochondrial fission links ECM mechanotransduction to metabolic redox homeostasis and metastatic chemotherapy resistance.
Nat Cell Biol
; 24(2): 168-180, 2022 02.
Article
in En
| MEDLINE
| ID: mdl-35165418
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.
Full text:
1
Collection:
01-internacional
Database:
MEDLINE
Main subject:
Breast Neoplasms
/
Drug Resistance, Neoplasm
/
Mechanotransduction, Cellular
/
Energy Metabolism
/
Extracellular Matrix
/
Mitochondrial Dynamics
/
Lung Neoplasms
/
Mitochondria
/
Antineoplastic Agents
Type of study:
Prognostic_studies
Language:
En
Journal:
Nat Cell Biol
Year:
2022
Document type:
Article
Affiliation country:
Italy