Cell shape, and not 2D migration, predicts extracellular matrix-driven 3D cell invasion in breast cancer
Cell shape, and not 2D migration, predicts extracellular matrix-driven 3D cell invasion in breast cancer
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DOI：
10.1063/1.5143779
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发表时间：
2020-06-01
影响因子：
6
通讯作者：
Oudin, Madeleine J.
中科院分区：
文献类型：
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作者：
Baskaran, Janani P.;Weldy, Anna;Oudin, Madeleine J.
转移是癌症患者死亡的主要原因，它需要肿瘤细胞响应迁移信号通过基质侵入，部分由细胞外基质（ECM）提供。蛋白质组学的最新进展已经导致数百种ECM蛋白的鉴定，相对于健康组织，它们在肿瘤中更为丰富。我们的目标是开发一个管道，以轻松预测哪些ECM蛋白更有可能对癌症侵袭和转移产生影响。我们通过三个实验评估了四种上调的ECM蛋白在多种人类乳腺癌细胞系乳腺肿瘤组织中的作用。细胞粘附到ECM蛋白与ECM驱动的二维细胞迁移速度、持久性或三维侵袭之间没有线性关系。然后，我们使用分类器和偏最小二乘回归分析来确定哪些指标最能预测ecm驱动的2D迁移和3D入侵响应。我们发现，ecm驱动的2D细胞迁移速度或持久性并不能预测相同提示下的3D入侵。然而，细胞粘附，特别是细胞伸长和形状不规则，准确地预测了ecm驱动的二维迁移和三维侵袭的大小。我们的模型成功地以细胞系特异性的方式预测了新型ECM蛋白的作用。总的来说，我们的研究确定了细胞形态特征，这些特征决定了对单个ECM蛋白的3D入侵反应。该平台将有助于深入了解肿瘤组织中丰富的ECM蛋白的功能作用，并有助于优先考虑针对肿瘤-ECM相互作用治疗转移的策略。
Metastasis, the leading cause of death in cancer patients, requires the invasion of tumor cells through the stroma in response to migratory cues, in part provided by the extracellular matrix (ECM). Recent advances in proteomics have led to the identification of hundreds of ECM proteins, which are more abundant in tumors relative to healthy tissue. Our goal was to develop a pipeline to easily predict which ECM proteins are more likely to have an effect on cancer invasion and metastasis. We evaluated the effect of four ECM proteins upregulated in breast tumor tissue in multiple human breast cancer cell lines in three assays. There was no linear relationship between cell adhesion to ECM proteins and ECM-driven 2D cell migration speed, persistence, or 3D invasion. We then used classifiers and partial-least squares regression analysis to identify which metrics best predicted ECM-driven 2D migration and 3D invasion responses. We find that ECM-driven 2D cell migration speed or persistence did not predict 3D invasion in response to the same cue. However, cell adhesion, and in particular cell elongation and shape irregularity, accurately predicted the magnitude of ECM-driven 2D migration and 3D invasion. Our models successfully predicted the effect of novel ECM proteins in a cell-line specific manner. Overall, our studies identify the cell morphological features that determine 3D invasion responses to individual ECM proteins. This platform will help provide insight into the functional role of ECM proteins abundant in tumor tissue and help prioritize strategies for targeting tumor-ECM interactions to treat metastasis.