Extracellular Matrix Elasticity Promotes Metastatic Therapy Resistance

During disease progression of solid tumors, including breast cancer, cancer cells interact with an increasingly stiff extracellular matrix (ECM) in the microenvironment of the primary tumor, whereas cancer cells that disseminate to distant organs encounter a relatively soft ECM. Mechanical properties of the local tissue microenvironment can affect cell behavior through signaling cascades, but whether a shift from stiff to soft ECM during metastatic development can influence therapeutic response remains unknown. To investigate this question, Romani and colleagues experimentally mimicked the decreased cell contractility observed on a soft ECM by treating transformed human mammary epithelial (MCF10A-Ras) cells with Rho-associated kinase and myosin light chain kinase inhibitors or by culturing cells on soft versus stiff hydrogels, showing that a soft ECM increases glutathione metabolism. In MCF10A-Ras cells, as well as D2.0R mouse metastatic breast cancer cells, a soft ECM induced an NRF2-driven antioxidant program that was mediated primarily by mitochondrial reactive oxygen species (ROS) and conferred tolerance to oxidative stress. Notably, a soft ECM altered mitochondrial network morphology, increasing DRP1-mediated mitochondrial fission, with this change in mitochondrial dynamics resulting from enhanced formation of perimitochondrial F-actin and leading to increased DRP1 activity. To study the impact of these phenotypes in response to therapy in vitro, D2.0R cells were treated with cisplatin or arsenic trioxide—chemotherapies that cause cytotoxicity through oxidative stress—revealing that a soft ECM promoted therapeutic resistance, which could be reversed with inhibition of Nrf2 or Drp1. Metastatic D2.0R cells were transplanted into mice to explore these observations in vivo, and atomic force microscopy analysis confirmed that early metastatic dissemination to the lung occurs in a soft microenvironment. Cisplatin treatment during the early phase of metastasis did not prevent dormant cells from developing into overt metastases, whereas treatment in the context of Nrf2 or Drp1 knockdown markedly reduced metastatic cell growth. In summary, this work highlights how an adaptive response to mechanical changes in ECM confers resistance to ROS-dependent therapies.

Romani P, Nirchio N, Arboit M, Barbieri V, Tosi A, Michielin F, et al. Mitochondrial fission links ECM mechanotransduction to metabolic redox homeostasis and metastatic chemotherapy resistance. Nat Cell Biol 2022;24:168–80.

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