Cancer cell unjamming and jamming as prerequisite for the formation of primary and metastatic tumors

病理改变，如发育不良或瘤变引起形态改变，诱导紊乱作为早期运动转变，集体传播细胞到人体。我们最近的研究表明，癌细胞解除干扰会显著增加远处转移的风险。机械生物学证明，纤维化基质作为肿瘤启动子，将细胞转化为更具侵略性的表型，可能有利于解除干扰。根据我们最近对乳腺癌和宫颈癌的研究，肿瘤中的癌细胞簇呈现一种混合状态，主要是柔软的未堵塞的细胞，形成具有增加组织流动性的运动区域，而少数刚性堵塞的细胞保持非运动状态。它们共同形成了一种新的组织悖论状态，在这种状态下，肿瘤通过细胞增殖获得了取代周围健康组织的坚实抵抗力，并且在流体中获得了有利于细胞在致密组织中迁移的自由度。解除干扰如何调节肿瘤组织中涌现的多尺度流动性、非均质性和固体应力目前尚不清楚。最近的研究结果特别表明，循环肿瘤细胞的播散/嵌套可能取决于干扰的解除。我们提出了一种简单的微流体系统，它模拟肝脏的血管系统，结合脱细胞组织基质，以确定在流动性、机械异质性和固体应力方面解除和堵塞的机械MRE特征。解除干扰可促进癌细胞在转移过程中逃逸，干扰可促进转移性嵌套。我们的假设是，癌细胞解除干扰/干扰转变是集体细胞生物力学的先决条件，癌细胞可以从肝脏和胰腺的ECM中逃逸或巢在血管系统中。我们将使用我们最近导出的状态图，该图使用细胞和细胞核形状以及核数密度作为变量，在显微镜下检测干扰/解除干扰，并将其与从患者来源的胰腺和肝脏肿瘤中提取的细胞的组织尺度MRE特征相关联。在工作包1 （WP 1）中设置我们的微流控分析后，将在我们的微流控室中平行进行包（WP 2-4）。我们将根据解除干扰/干扰来测量：癌细胞在流动中聚集和生长（WP 2），在流动中去细胞化的ECM中聚集/生长（WP 3），以及细胞在流动中从嵌入去细胞化基质的细胞聚集体中传播（WP 4）。在WP 2-4中，我们最终将使用高度异质性的原发肿瘤细胞（肝脏、胰腺）来确定有利于癌细胞逃逸和筑巢的细胞表型。这些测量将与桌面MRE测量（WP 5）相关联。这个子项目的具体贡献是确定癌细胞解除干扰/干扰在肝脏和胰腺肿瘤形成和转移扩散中的机械特征。

Pathological changes such as dysplasia or neoplasia cause morphological changes that induce unjamming as an early motility transition to collectively disseminate cells into the human body. We have recently shown that cancer cell unjamming significantly increases distant metastatic risk. Mechanobiology demonstrates that fibrotic stroma acts as tumor promoter and transforms cells into a more aggressive phenotype that may favor unjamming. According to our recent studies in breast and cervix carcinoma, cancer cell clusters in tumors assume a hybrid state of predominantly soft unjammed cells that form motile regions with an increased tissue fluidity and a few rigid jammed cells that remain in a non-motile state. Together they form a new paradox state of tissues in which a tumor acquires the solid resistance to displace surrounding healthy tissue by cell proliferation and the degrees of freedom as in a fluid to favor cell migration through dense tissues. How unjamming modulates emergent multiscale fluidity, heterogeneity, solid stress in tumor tissue is by far not understood. Recent results particularly indicate that dissemination/nesting of circulating tumor cells may depend on unjamming. We propose a simple microfluidic system that mimics the vasculature of the liver in conjunction with a decellularized tissue matrix to determine the mechanical MRE signature of unjamming and jamming in terms of fluidity, mechanical heterogeneity and solid stress. Cancer cell escape in metastasis may be fostered by unjamming and metastatic nesting by jamming. Our hypothesis is that cancer cell unjamming/jamming transitions are collective cellular biomechanical prerequisites that cancer cells can escape from or nest in the ECM of the liver and pancreas with respect to the vasculature. We will use our recently derived state diagram that uses cell and nucleus shape as well as nucleus number density as variables to microscopically detect jamming/unjamming and correlate it with the according tissue scale MRE signature for cells taken from patient derived pancreas and liver tumors. After setting up our microfluidic assay in work package 1 (WP 1) the packages (WP 2-4) will be pursued in parallel in our microfluidic chamber. We will measure depending on unjamming/jamming: cancer cell aggregation and growth in flows (WP 2), and aggregation/ growth in decellularized ECM under flows (WP 3), and cell dissemination under flow from cell aggregates embedded in decellularized matrix (WP 4). In WP 2-4 we will ultimately use highly heterogeneous primary tumor cells (liver, pancreas) to determine cell phenotypes that favor cancer cell escape and nesting. These measurements will be correlated with table top MRE measurements (WP 5). It is the specific contribution of this subproject to determine the mechanical signatures of cancer cell unjamming/jamming in hepatic and pancreatic tumor formation and metastatic spread.