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

癌细胞的解干扰和干扰是原发性和转移性肿瘤形成的先决条件

• 批准号: 530848063
• 负责人: Professor Dr. Josef Alfons Käs
• 金额: --
• 依托单位: Abteilung Physik der weichen Materie
• 依托单位国家: 德国
• 项目类别: Research Units
• 资助国家: 德国
• 项目状态: 未结题
• 来源: https://gepris.dfg.de/gepris/projekt/530848063?language=en
• 关键词: Cancer; cell; unjamming; jamming; prerequisite

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.

病理变化如发育异常或瘤形成引起形态学变化，其诱导解除干扰作为早期运动性转变以将细胞集体散布到人体中。我们最近发现，癌细胞解除干扰显著增加了远处转移的风险。机械生物学表明，纤维化间质作为肿瘤促进剂，并将细胞转化为更积极的表型，可能有利于解除干扰。根据我们最近在乳腺癌和宫颈癌中的研究，肿瘤中的癌细胞簇呈现主要是软未堵塞细胞的混合状态，其形成具有增加的组织流动性的运动区域和少数保持在非运动状态的刚性堵塞细胞。它们一起形成了一种新的组织悖论状态，其中肿瘤获得了通过细胞增殖取代周围健康组织的固体抵抗力，以及流体中的自由度，以促进细胞迁移通过致密组织。解除干扰如何调节肿瘤组织中出现的多尺度流动性、异质性和固体应力，目前尚不清楚。最近的结果特别表明，循环肿瘤细胞的传播/嵌套可能取决于解除干扰。我们提出了一个简单的微流体系统，它模仿肝脏的血管系统与脱细胞组织基质结合，以确定流动性，机械异质性和固体应力方面的机械MRE签名。转移中的癌细胞逃逸可以通过解除阻塞来促进，转移嵌套可以通过阻塞来促进。我们的假设是，癌细胞解除干扰/干扰转换是癌细胞可以从肝脏和胰腺的ECM中逃逸或嵌套在血管系统中的集体细胞生物力学先决条件。我们将使用我们最近导出的状态图，该状态图使用细胞和细胞核形状以及细胞核数密度作为变量，以显微镜检测堵塞/解除堵塞，并将其与取自患者来源的胰腺和肝脏肿瘤的细胞的相应组织尺度MRE特征相关联。在工作包1（WP 1）中建立我们的微流体测定之后，将在我们的微流体室中并行地进行包（WP 2-4）。我们将根据解除干扰/干扰来测量：流动中的癌细胞聚集和生长（WP 2），流动下的脱细胞ECM中的聚集/生长（WP 3），以及来自包埋在脱细胞基质中的细胞聚集体的流动下的细胞散布（WP 4）。在WP 2-4中，我们最终将使用高度异质性的原发性肿瘤细胞（肝脏，胰腺）来确定有利于癌细胞逃逸和嵌套的细胞表型。这些测量值将与台面MRE测量值（WP 5）相关联。该子项目的具体贡献是确定肝和胰腺肿瘤形成和转移扩散中癌细胞解除干扰/干扰的机械特征。