Extracellular matrix biophysical cues in dormancy and bone metastasis

合成细胞指导材料允许独立控制生物物理特性，并有助于理解细胞如何感知细胞外基质（ECM）在组织再生中的生物物理线索。材料科学方法也被用于研究癌症进展的不同步骤，如肿瘤生长、归巢或转移。乳腺癌是全世界妇女癌症相关死亡的主要原因之一。乳腺癌经常转移到骨，甚至可能在肿瘤切除后20-25年发生。这意味着癌细胞可以经历一个休眠期。已经确定了三种机制：(i)孤立细胞休眠，（ii）血管生成性肿瘤休眠（细胞凋亡平衡的细胞分裂）和（iii）逃避免疫监视。在孤立细胞的休眠中，与周围基质的相互作用是关键。然而，ECM生物物理信号在休眠和再激活中的作用尚不清楚，部分原因是缺乏良好的体外和体内模型。我们假设ECM调节骨髓中孤立的乳腺癌细胞的休眠：癌细胞增殖在应激信号下被激活，以改变的ECM生物物理特性的形式被感知，如果体内平衡恢复，它们可以恢复休眠。本项目的目标是通过(i)合成仿生细胞微环境和（ii）开发表征和成像方法来研究体内早期转移和休眠生态位，从而有助于理解生物物理机制如何调节休眠和骨转移中的细胞-基质相互作用。我们之前已经开发了用于组织工程的合成材料，并使用先进的材料科学方法来表征体内再生的软组织和矿化组织。为了验证我们的假设，我们将合成人工细胞壁龛来识别休眠和增殖的物理线索（WP 1）。这将为使用成骨细胞或内皮细胞共培养（WP 2）来模拟骨内和血管周围生态位的器官型2D和3D微环境的发展奠定基础。合成微环境的设计将受到早期转移和休眠生态位的体内观察以及相关的ECM微观结构和组成的多尺度表征（WP 3）的启发。将开发一种活体成像方法来检测骨髓中的活肿瘤细胞，它们的空间分布和休眠与增殖状态（WP 4）。为了定量描述体外实验数据（WP 1, WP 2），将创建一个数值模型来描述肿瘤细胞聚集和组织扩散与生长停滞。对ECM生物物理信号在休眠和骨转移中的作用的进一步了解可能会导致新的治疗方法，例如提供信号以确保休眠状态，或消灭生态位以及随之而来的癌细胞库。

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.