Mechanical adaptation of metastatic cancer cells during organ colonization <i>in vivo</i>

Metastasis defines the spread of primary tumors to distant organs. The metastatic process is a complex process involving genomic, biochemical and mechanical perturbations. Interestingly, different types of primary cancers preferentially metastasize to specific distal organs (organotropism), which cannot be explained solely by circulatory dynamics. One idea is that successful outgrowth depends on the ability of cancer cells to tune their mechanical properties to match the local mechanical properties of the organ. Here, we aim to understand the biomechanical adaptation of cancer cells at the mesoscale in the later stage of metastasis and its role in organotropism in vivo. Specifically, this study aims to identify unique mechanical drivers of extravasation in the brain that could be targeted to inhibit brain metastasis in breast cancer patients. We measured the intracellular rheological properties of malignant cells in vitro using optical tweezer active microrheology in vivo using zebrafish as a model for cancer metastasis. We present that cancer cells conditioned in different stiffnesses in vitro and in distant organs in vivo show distinct mechanical properties that also differ from that of the parental cell line. We also determined that breast cancer and melanoma cells soften after extravasation into the brain parenchyma in comparison to pre-extravasation. However, cells stiffen at one day post extravasation in vivo to match that of the local microenvironment. During extravasation process, cancer cells become more liquid-like and semi-flexible. Future work will focus on genetic regulation of this mechanical adaptation.