Assessing the roles of collagen fiber morphology and matrix stiffness on ovarian cancer cell migration dynamics using multiphoton fabricated orthogonal image-based models.
Assessing the roles of collagen fiber morphology and matrix stiffness on ovarian cancer cell migration dynamics using multiphoton fabricated orthogonal image-based models.
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DOI：
10.1016/j.actbio.2022.09.037
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发表时间：
2022-11
影响因子：
9.7
通讯作者：
中科院分区：
文献类型：
--
作者：
卵巢癌仍然是最致命的妇科癌症，这是由于可以检测早期疾病的筛查和成像工具差，以及对肿瘤微环境的结构和功能方面的了解有限。为了深入了解潜在的细胞动力学，我们使用多光子激发制造来从胶原/GelMA创建基于二次谐波生成图像的正交模型，其代表正常卵巢基质和高级别浆液性卵巢癌（HGSOC）的胶原基质形态和硬度（~2-8 kPa）。这些支架用于研究正常（IOSE）和卵巢癌（OVCA 433）细胞系的迁移/细胞骨架动力学。我们发现，HGSOC的高度对齐的纤维形态通过接触引导机制促进运动性（运动系数、运动性和粘着斑表达）方面，并且更硬的基质通过机械敏感机制进一步促进这些相同的过程，其中这些趋势对于正常细胞和癌细胞都是相似的。然而，在这些正交模型上发现了细胞特异性差异，相对于仅提供形态的那些，显示了呈现形态和刚度线索的重要性。此外，我们发现增加钙粘蛋白的表达和减少细胞排列只为癌细胞的支架上的中间模量，表明不同的刚度依赖性mechanotransductionmechanism参与。这种整体方法提供了解耦的作用，基质形态，硬度和细胞基因型，并提供假设检验的因素引起疾病的进展和转移。此外，更成熟的制造技术不能同时再现3D胶原纤维形态和刚度。
Ovarian cancer remains the deadliest of the gynecological cancers, where this arises from poor screening and imaging tools that can detect early disease, and also limited understanding of the structural and functional aspects of the tumor microenvironment. To gain insight into the underlying cellular dynamics, we have used multiphoton excited fabrication to create Second Harmonic Generation image-based orthogonal models from collagen/GelMA that represent both the collagen matrix morphology and stiffness (~2-8 kPa) of normal ovarian stroma and high grade serous ovarian cancers (HGSOC). These scaffolds are used to study migration/cytoskeletal dynamics of normal (IOSE) and ovarian cancer (OVCA433) cell lines. We found that the highly aligned fiber morphology of HGSOC promotes aspects of motility (motility coefficient, motility, and focal adhesion expression) through a contact guidance mechanism and that stiffer matrix further promotes these same processes through a mechanosensitive mechanism, where these trends were similar for both normal and cancer cells. However, cell specific differences were found on these orthogonal models relative to those providing only morphology, showing the importance of presenting both morphology and stiffness cues. Moreover, we found increased cadherin expression and decreased cell alignment only for cancer cells on scaffolds of intermediate modulus suggesting different stiffness-dependent mechanotransduction mechanisms are engaged. This overall approach affords decoupling the roles of matrix morphology, stiffness and cell genotype and affords hypothesis testing of the factors giving rise to disease progression and metastasis. Further, more established fabrication techniques cannot simultaneously reproduce both the 3D collagen fiber morphology and stiffness.
影响因子：
2.8
作者：
Chen, Xiyi;Su, Yuan-Deng;Ajeti, Visar;Chen, Shean-Jen;Campagnola, Paul J.
通讯作者：
Campagnola, Paul J.