PDF(Pubmed)
Abstract：
Pancreatic ductal adenocarcinoma (PDAC) is a solid-tumor malignancy. To enhance the treatment landscape of PDAC, a 3D model optimized for rigorous drug screening is essential. Within the PDAC tumor microenvironment, a dense stroma comprising a large extracellular matrix and cancer-associated fibroblasts (CAFs) is well-known for its vital role in modulating tumor growth, cellular heterogeneity, bidirectional paracrine signaling, and chemoresistance. In this study, we employed a fibroblast-populated collagen lattice (FPCL) modeling approach that has the ability to replicate fibroblast contractility in the collagenous matrix to build dense stroma. This FPCL model allows CAF differentiation by facilitating multifaceted cell-cell interactions between cancer cells and CAFs, with the differentiation further influenced by mechanical forces and hypoxia carried within the 3D structure. Our FPCL models displayed hallmark features, including ductal gland structures and differentiated CAFs with spindle shapes. Through morphological explorations alongside in-depth transcriptomic and metabolomic profiling, we identified substantial molecular shifts from the nascent to mature model stages and potential metabolic biomarkers, such as proline. The initial pharmacological assays highlighted the effectiveness of our FPCL model in screening for improved therapeutic strategies. In conclusion, our PDAC modeling platform mirrors complex tumor microenvironmental dynamics and offers an unparalleled perspective for therapeutic exploration.
摘要：
胰腺导管腺癌（PDAC）是一种实体瘤恶性肿瘤。为了加强PDAC的治疗景观，为严格的药物筛选而优化的3D模型至关重要.在PDAC肿瘤微环境中，由大量细胞外基质和癌症相关成纤维细胞（CAFs）组成的致密基质因其在调节肿瘤生长中的重要作用而闻名，细胞异质性，双向旁分泌信号，和化学抗性。在这项研究中,我们采用了成纤维细胞填充的胶原晶格(FPCL)建模方法,该方法能够在胶原基质中复制成纤维细胞收缩性,以构建致密基质.这种FPCL模型通过促进癌细胞和CAF之间的多方面细胞间相互作用来实现CAF分化。分化进一步受到3D结构内的机械力和缺氧的影响。我们的FPCL模型显示了标志性特征，包括导管腺结构和具有纺锤形的分化CAF。通过形态学探索以及深入的转录组学和代谢组学分析，我们确定了从新生到成熟模型阶段的大量分子转移和潜在的代谢生物标志物，如脯氨酸。最初的药理学测定强调了我们的FPCL模型在筛选改进的治疗策略中的有效性。总之,我们的PDAC建模平台反映了复杂的肿瘤微环境动力学，并为治疗探索提供了无与伦比的视角。
