Extracellular matrix biophysical cues in dormancy and bone metastasis

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Synthetic cell instructive materials allow independent control of biophysical properties and have contributed to the understanding, how cells sense extracellular matrix (ECM) biophysical cues in tissue regeneration. Materials science approaches have also been used to investigate different steps in cancer progression, such as tumor growth, homing or metastasis. Breast cancer is one of the leading causes of cancer-associated deaths among women worldwide. Breast cancer often metastasizes to bone, which can occur even after 20-25 years following tumor resection. This implies that cancer cells can undergo a dormancy phase. Three mechanisms have been identified: (i) dormancy of solitary cells, (ii) angiogenic tumor dormancy (cell division balanced by apoptosis) and (iii) escape from immunosurveillance. In dormancy of solitary cells the interaction with the surrounding matrix is pivotal. However, the role of ECM biophysical cues in dormancy and reactivation is poorly understood, in part due to a lack of good in-vitro and in-vivo models. We hypothesize that the ECM regulates dormancy of solitary breast cancer cells in the bone marrow: cancer cell proliferation is activated under stress signals, perceived in form of altered ECM biophysical properties, and they can return to dormancy, if homeostasis is restored. The goal of this project is to contribute to the understanding, how biophysical mechanisms regulate cell-matrix interaction in dormancy and bone metastasis, by (i) synthesizing biomimetic cell microenvironments and (ii) developing characterization and imaging methods to study the early metastatic and dormant niche in-vivo. We have previously developed synthetic materials for tissue engineering and have used advanced materials science methods to characterize regenerated soft and mineralized tissue in-vivo. To test our hypothesis we will synthesize artificial cell niches to identify dormancy vs. proliferative physical cues (WP 1). This will lay the basis for the development of organotypic 2D and 3D microenvironments as mimics of the endosteal and perivascular niches using osteoblast or endothelial cell co-cultures (WP 2). The design of the synthetic microenvironments will be inspired on in-vivo observations of the early metastatic and dormant niches, and correlative, multiscale characterization of the microstructure and composition of the ECM (WP 3). An intra-vital imaging methodology will be developed to detect live tumor cells in the bone marrow, their spatial distribution and dormant vs. proliferative state (WP 4). For quantitative description of in-vitro experimental data (WP 1, WP 2), a numerical model will be created to describe tumor cell clustering and tissue spreading vs. growth arrest. An improved understanding of the role of ECM biophysical cues in dormancy and bone metastasis could lead to novel therapeutic approaches, such as to provide cues to ensure a dormant state, or to annihilate the niche and, with it, the cancer cell reservoir.