A mathematical model of tumor-endothelial interactions in a 3D co-culture
A mathematical model of tumor-endothelial interactions in a 3D co-culture
复制标题
DOI：
10.1038/s41598-019-44713-2
复制
发表时间：
2019-06-10
影响因子：
4.6
通讯作者：
Sengupta, Shiladitya
中科院分区：
文献类型：
--
作者：
Connor, Yamicia;Tekleab, Yonatan;Sengupta, Shiladitya
癌细胞通过血管/淋巴管内皮的内渗和外渗是转移过程中的重要步骤。成功的侵袭需要协调的肿瘤-内皮串扰，利用机械化学信号传导来指导cytokeretaI重排以使癌细胞迁移。然而，物理相互作用的机制很难观察到，由于缺乏容易与理论模型相结合，更好地阐明这些途径的实验模型。我们之前已经证明，工程化的3D体外内皮-上皮共培养系统可用于在易于建模、定量和探测实验研究的平台中分离分子和物理肿瘤-内皮相互作用。使用这个平台与数学建模，我们表明，乳腺转移细胞显示出独特的行为与内皮细胞，表现出3.2倍的增加与内皮细胞的相互作用和61倍的延长相比，正常乳腺上皮细胞。我们的数学模型表明，在破坏内皮连接之前，细胞变形的能量可吸收性，与未变形的细胞相比，消耗更少的能量，这与观察到的表型一致。最后，我们实验表明，药理学抑制的细胞骨架可以破坏的elongancing和对齐的转移细胞与内皮管，恢复到一个较低的侵入性表型。
Intravasation and extravasation of cancer cells through blood/lymph vessel endothelium are essential steps during metastasis. Successful invasion requires coordinated tumor-endothelial crosstalk, utilizing mechanochemical signaling to direct cytoskeleta I rearrangement for transmigration of cancer cells. However, mechanisms underlying physical interactions are difficult to observe due to the lack of experimental models easily combined with theoretical models that better elucidate these pathways. We have previously demonstrated that an engineered 3D in vitro endothelial-epithelial co-culture system can be used to isolate both molecular and physical tumor-endothelial interactions in a platform that is easily modeled, quantified, and probed for experimental investigation. Using this platform with mathematical modeling, we show that breast metastatic cells display unique behavior with the endothelium, exhibiting a 3.2-fold increase in interaction with the endothelium and a 61-fold increase in elongation compared to normal breast epithelial cells. Our mathematical model suggests energetic favorability for cellular deformation prior to breeching endothelial junctions, expending less energy as compared to undeformed cells, which is consistent with the observed phenotype. Finally, we show experimentally that pharmacological inhibition of the cytoskeleton can disrupt the elongatation and alignment of metastatic cells with endothelial tubes, reverting to a less invasive phenotype.