PEG-peptide hydrogels reveal differential effects of matrix microenvironmental cues on melanoma drug sensitivity.
PEG-peptide hydrogels reveal differential effects of matrix microenvironmental cues on melanoma drug sensitivity.
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PEG肽水凝胶揭示了基质微环境线索对黑色素瘤药物敏感性的不同影响。
DOI：
10.1039/c6ib00229c
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发表时间：
2017-01-23
期刊：
影响因子：
--
通讯作者：
Anseth KS
中科院分区：
文献类型：
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作者：
Tokuda EY;Jones CE;Anseth KS
转移性黑色素瘤是高度耐药的，尽管这种耐药的确切机制还不完全清楚。体外研究黑素瘤药物反应性的一种方法是通过使用多细胞球状体，已经发现与在各种基质上的传统2D培养物相比，多细胞球状体表现出降低的药物敏感性。由于尚不清楚维度、细胞-基质相互作用和/或细胞-细胞接触是否可能影响黑素瘤药物反应性，我们利用合成的基于PEG的水凝胶来比较在具有相同粘附配体密度、聚合物密度和材料性质的基质上培养或包封的细胞的反应。我们发现，根据黑色素瘤细胞来源的进展阶段，细胞对PLX 4032治疗（一种市售的黑色素瘤药物）的反应不同。具体地，早期阶段的WM 35细胞对维度不敏感（即，2D与3D培养），而转移性A375细胞在3D中表现出与2D相比降低的反应性。为了进一步了解微环境对早期黑素瘤细胞的作用，我们在3D中测试了单个WM 35细胞和多细胞WM 35球体。结果显示，与单细胞培养物相比，球状体对PLX 4032处理的敏感性相似。总的来说，这项研究暗示了3D微环境（即，维度）可能在观察到的黑素瘤药物响应性中起作用，并且在黑素瘤对PLX 4032诱导的细胞凋亡的抗性的早期阶段中细胞-基质相互作用对细胞-细胞接触的影响的潜在缺乏。评估了系统性微环境变化对黑色素瘤药物反应性的影响，发现其取决于进展阶段和培养条件。
Metastatic melanoma is highly drug resistant, though the exact mechanisms of this resistance are not completely understood. One method to study melanoma drug responsiveness in vitro is through the use of multicellular spheroids, which have been found to exhibit decreased drug sensitivity compared to traditional 2D culture on various substrates. Because it is unclear whether dimensionality, cell-matrix interactions, and/or cell-cell contacts may influence melanoma drug responsiveness, we utilized a synthetic PEG-based hydrogel to compare the responses of cells cultured on top of or encapsulated within matrices with the same adhesive ligand density, polymer density, and material properties. We found that depending on the stage of progression with which the melanoma cells were derived, the cells responded differently to PLX4032 treatment, a commercially available melanoma drug. Specifically, early stage WM35 cells were insensitive to dimensionality (i.e., 2D versus 3D culture), while metastatic A375 cells exhibited decreased responsiveness in 3D compared to 2D. To further understand the role of the microenvironment on early stage melanoma cells, we tested single WM35 cells and multicellular WM35 spheroids in 3D. Results revealed that the spheroids were similarly sensitive to PLX4032 treatment compared to single cell encapsulations. Collectively, this study implicates the role that 3D microenvironments (i.e., dimensionality) may play in observed melanoma drug responsiveness, and the potential lack of influence of cell-matrix interactions over cell-cell contacts in early stages of melanoma resistance to PLX4032-induced apoptosis. The effects of systematic microenvironmental changes on melanoma drug responsiveness were assessed and found to depend on the stage of progression and culture conditions.