Invited Talk

Biomechanical Tumor-Matrix Interactions in Breast Cancer Invasion

UT Dallas, Dept. of Bioengineering, 800 West Campbell Rd., TX 75080-3021, Dallas, USA

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It is well established that the tumor microenvironment is both a cause and a consequence of malignant phenotypes in breast cancer, though the exact biophysical mechanisms underlying different modalities of invasion remain unclear. The biomechanical properties of the extracellular matrix (ECM) play key roles in both early-stage and advanced breast cancer. Analysis of tumor-matrix interactions are complicated by the fact that the collagenous ECM is not just a static substrate but rather a dynamic scaffold that is actively remodeled by biochemical and biomechanical activity of cancer and stromal cells. Furthermore, depending on the material properties of constituent cells and of the ECM, breast cancer cells can invade as single cells or as multicellular collectives. By combining organotypic in vitro spheroids and in silico computational models, we investigated the biomechanical remodeling of peritumoral collagen and the evolution of distinct material phases during invasion into 3D collagen network. First, we show that growth of epithelial cancers induces compressive remodeling of the ECM, which represents a localized densification and tangential alignment of peritumoral collagen. Such compressive remodeling is caused by the unique features of collagen network mechanics, such as fiber buckling and cross-link rupture. Second, we show that breast cancer spheroids develop intratumoral heterogeneities in material phase which ultimately result in a variety of phase separation patterns at the invasive front. Depending upon cell type and collagen density, cancer cells within the spheroid display a variety of collective behaviors, including a jammed solid-like phase and progressively unjammed liquid-like and gas-like phases. Our work highlights the fact that tumor-matrix interactions are spatially and temporally heterogeneous, hence there is a pressing need to develop new biomechanical tools that will improve our mechanistic understanding of breast cancer invasion.