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

Abstract

Metastatic breast cancer cells disseminate to organs with a soft microenvironment. Whether and how local tissue mechanical properties influence their response to treatment remains unclear. Here we found that a soft ECM empowers redox homeostasis. Cells cultured on a soft ECM 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 mtROS production 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 ROS-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.

AMPK is a mechano-metabolic sensor linking cell adhesion and mitochondrial dynamics to Myosin II dependent cell migration

“…Matrix architecture in uences cellular energetics [32][33][34][35] and ECM stiffness has been linked to glycolysis 34 and mitochondrial reprogramming 36 in normal epithelial cells. Also, changes in the ECM stiffness alter mitochondrial dynamics and triggers an enhanced redox response 36,37 . We describe here how AMPK and mitochondrial dynamics operate in cancer cells in physiological 3D matrices to provide the cytoskeletal plasticity required for e cient cell migration.…”

The Interplay between Cell-Extracellular Matrix Interaction and Mitochondria Dynamics in Cancer

“…Soft ECM enhances mitochondria fission due to increased expression of DRP1 and mitochondria elongation factor 1 and 2 (MIEF1/2). In this case, mitochondria fission increases both the production of mtROS and the activity of NRF2 antioxidant transcriptional response, therefore cells increase their tolerance to oxidative stress [53]. It will be interesting to investigate the signaling pathways that are involved in this process.…”

ELK3 modulates the antitumor efficacy of natural killer cells against triple negative breast cancer by regulating mitochondrial dynamics

“…[17][18][19] Recent studies demonstrated that Mid51 plays pivotal roles in cancer initiation, progression, metastatic chemotherapy resistance, and poor prognosis. [20][21][22] Although Yap-JNK axis, Yap-Hippo axis, and TAZ are known regulators of Mid51 expression in various cancers, including thyroid carcinoma, colorectal cancer, and lung cancer, [20][21][22][23] the transcription factors that directly bind to the Mid51 promoter to regulate its activity have not yet been identified. E26 transformation-specific transcription factor ELK3 (ELK3) is a ternary complex factor subfamily E26 transformation specific (ETS) protein characterized by its ability to form a ternary nucleoprotein complex with the serum response factor on the serum response element present in the c-fos promoter.…”