Lung Rheology Responds Differently to Chemotherapy-induced or Native Tumor-derived Microparticles

Tamar Barenholz Cohen 1 Daniela Kirchmeier 1,3 Jozafina Haj 2 Yuval Shaked 2 Daphne Weihs 1
1Technion – Israel Institute of Technology, Israel
2Technion – Israel Institute of Technology, Israel
3University of Applied Sciences, Austria

The mechanics of the tumor microenvironment greatly affects the cell and whole tumor growth rate, the tumor cells’ invasive capacity, and their survival following treatment. Following chemotherapy, tumor cells respond by shedding increased numbers of tumor-derived microparticles (TMPs). It has been shown those TMPs support tumor growth. However, the physical and mechanobiological changes in the pre-metastatic sites which support tumor cell seeding have not been determined. Here, we have evaluated the effects of TMPs shed from breast cancer cells and TMPs treated with paclitaxel on rheology of organs in cancer-free mice. We measure various mechanical properties (e.g. elasticity and stiffness) of the tissue slices using shear rheometry. We observe that mouse lungs are in general viscoelastic with mucosal-like rheology. Following the in vivo exposure to control TMPs, we observe a wide range of stiffness both between mice and within slices from the same mouse; this shows the heterogeneity of the lung structure. In contrast, in lung slices from mice exposed to chemotherapy-induced TMPs we observe reduced and more homogenous stiffness. Furthermore, we observe statistically significant differences in the residual plasticity induced in the different samples when physiological-level deformations are induced; those relate e.g. to normal and heavy breathing cycles. Specifically, lungs expose to chemotherapy-induced TMPs are less compliant, they show less change in stiffness under low and high strains. Our results demonstrate that exposure to TMP induces changes in tissue (even) when cancer cells are not present in the body. These changes may indicate preparation of tumor-favorable pre-metastatic changes at a distant site.

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