Hagey Laboratory of Pediatric Regenerative Medicine, Stanford University School of Medicine, Stanford, CA 94305, USA.
Cell Sciences Imaging Facility, Stanford University, Stanford, CA 94305, USA.
Cell Rep Med. 2023 Nov 21;4(11):101248. doi: 10.1016/j.xcrm.2023.101248. Epub 2023 Oct 20.
Pancreatic ductal adenocarcinoma (PDAC) is projected to become the second leading cause of cancer-related death. Hallmarks include desmoplasia with variable extracellular matrix (ECM) architecture and a complex microenvironment with spatially defined tumor, stromal, and immune populations. Nevertheless, the role of desmoplastic spatial organization in patient/tumor variability remains underexplored, which we elucidate using two technologies. First, we quantify ECM patterning in 437 patients, revealing architectures associated with disease-free and overall survival. Second, we spatially profile the cellular milieu of 78 specimens using codetection by indexing, identifying an axis of pro-inflammatory cell interactions predictive of poorer outcomes. We discover that clinical characteristics, including neoadjuvant chemotherapy status, tumor stage, and ECM architecture, correlate with differential stromal-immune organization, including fibroblast subtypes with distinct niches. Lastly, we define unified signatures that predict survival with areas under the receiver operating characteristic curve (AUCs) of 0.872-0.903, differentiating survivorship by 655 days. Overall, our findings establish matrix ultrastructural and cellular organizations of fibrosis linked to poorer outcomes.
胰腺导管腺癌 (PDAC) 预计将成为癌症相关死亡的第二大主要原因。其特征包括具有不同细胞外基质 (ECM) 结构的纤维变性和具有空间定义的肿瘤、基质和免疫群体的复杂微环境。然而，纤维变性空间组织在患者/肿瘤变异性中的作用仍未得到充分探索，我们使用两种技术阐明了这一点。首先，我们对 437 名患者的 ECM 模式进行了定量分析，揭示了与无病生存和总生存相关的结构。其次，我们使用索引共检测法对 78 个标本的细胞环境进行了空间分析，确定了一个具有预测较差预后的促炎细胞相互作用的轴。我们发现，临床特征，包括新辅助化疗状态、肿瘤分期和 ECM 结构，与不同的基质-免疫组织有关，包括具有不同生态位的成纤维细胞亚型。最后，我们定义了具有统一特征的签名，可以预测生存情况，接收器操作特征曲线 (AUC) 的范围为 0.872-0.903，可将生存期差异区分 655 天。总的来说，我们的研究结果确定了与较差预后相关的纤维化的基质超微结构和细胞组织。
