School of Materials Science and Engineering, UNSW Sydney, Sydney, NSW, 2052, Australia.
School of Chemistry Australian Centre for Nanomedicine, UNSW Sydney, Sydney, NSW, 2052, Australia.
Adv Biol (Weinh). 2021 Jun;5(6):e2000525. doi: 10.1002/adbi.202000525. Epub 2021 Mar 22.
Interfacial cues in the tumor microenvironment direct the activity and assembly of multiple cell types. Pancreatic cancer, along with breast and prostate cancers, is enriched with cancer-associated fibroblasts (CAFs) that activate to coordinate the deposition of the extracellular matrix, which can comprise over 90% of the tumor mass. While it is clear that matrix underlies the severity of the disease, the relationship between stromal-tumor cell assembly and cell-matrix dynamics remains elusive. Micropatterned hydrogels deconstruct the interplay between matrix stiffness and geometric confinement, guiding heterotypic cell populations and matrix assembly in pancreatic cancer. Interfacial cues at the perimeter of microislands guide CAF migration and direct cancer cell assembly. Computational modeling shows curvature-stress dependent cellular localization for cancer and CAFs in coculture. Regions of convex curvature enhance edge stress that activates a myofibroblast phenotype in the CAFs with migration and increased collagen I deposition, ultimately leading to a central "corralling" of cancer cells. Inhibiting mechanotransduction pathways decreases CAF activation and the associated corralling phenotype. Together, this work reveals how interfacial biophysical cues underpin aspects of stromal desmoplasia, a hallmark of disease severity and chemoresistance in the pancreatic, breast, and prostate cancers, thereby providing a tool to expand stroma-targeting therapeutic strategies.
肿瘤微环境中的界面线索指导多种细胞类型的活性和组装。胰腺癌与乳腺癌和前列腺癌一样，富含癌相关成纤维细胞 (CAF)，这些细胞会被激活以协调细胞外基质的沉积，而细胞外基质可以占到肿瘤质量的 90%以上。虽然基质是疾病严重程度的基础已经很清楚，但基质-肿瘤细胞组装和细胞-基质动力学之间的关系仍然难以捉摸。微图案化水凝胶解构了基质硬度和几何约束之间的相互作用，从而指导胰腺癌细胞的异质细胞群体和基质组装。微岛周边的界面线索指导 CAF 的迁移并指导癌细胞的组装。计算模型显示，在共培养物中，曲率-应力依赖性细胞定位存在于癌症细胞和 CAF 中。凸曲率区域增强边缘应力，从而激活 CAF 中的肌成纤维细胞表型，导致 CAF 迁移和胶原蛋白 I 沉积增加，最终导致癌症细胞的中央“聚集”。抑制机械转导途径会降低 CAF 的激活和相关的聚集表型。总之，这项工作揭示了界面生物物理线索如何支持基质纤维化的某些方面，这是胰腺、乳腺和前列腺癌疾病严重程度和化疗耐药性的标志，从而为扩展基质靶向治疗策略提供了工具。
