Lung mechanics modifications facilitating metastasis are mediated in part by breast cancer‐derived extracellular vesicles

Tumor microenvironment‐mechanics greatly affect tumor‐cell characteristics such as invasion and proliferation. We and others have previously shown that after chemotherapy, tumor cells shed more extracellular vesicles (EVs), leading to tumor growth and even spread, via angiogenesis and the mobilization of specific bone‐marrow‐derived cells contributing to metastasis. However, physical, mechanobiological and mechanostructural changes at premetastatic sites that may support tumor cell seeding, have yet to be determined. Here, we collected tumor‐derived extracellular vesicles (tEV) from breast carcinoma cells exposed to paclitaxel chemotherapy, and tested their effects on tissue mechanics (eg, elasticity and stiffness) of likely metastatic organs in cancer‐free mice, using shear rheometry. Cancer‐free mice were injected with saline or with tEVs from untreated cells and lung tissue demonstrated widely variable, viscoelastic mechanics, being more elastic than viscous. Contrastingly, tEVs from chemotherapy‐exposed cells induced more uniform, viscoelastic lung mechanics, with lower stiffness and viscosity; interestingly, livers were significantly stiffer than both controls. We observe statistically significant differences in softening of lung samples from all three groups under increasing strain‐amplitudes and in their stiffening under increasing strain‐frequencies; the groups reach similar values at high strain amplitudes and frequencies, indicating local changes in tissue microstructure. Evaluation of genes associated with the extracellular matrix and fibronectin protein‐expression revealed potential compositional changes underlying the altered mechanics. Thus, we propose that tEVs, even without cancer cells, contribute to metastasis by changing microstructures at distant organs. This is done partially by altering the composition and mechanostructure of tissues to support tumor cell invasion and seeding. What's new? Several studies have shown that under some circumstances, anti‐cancer therapy may promote metastasis spread. However, the underlying biomechanical changes at the pre‐metastatic sites have yet to be determined. Here, the authors show that tumor extracellular vesicles (tEVs) shed from breast cancer cells, especially after their exposure to chemotherapy, induce changes in the lung tissue mechanics of cancer‐free mice that may support cancer cell invasion and seeding. These changes include reduced stiffness and plasticity in lungs. Overall, the results r