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Abstract：
Pancreatic ductal adenocarcinoma (PDAC) remains one of the most lethal malignancies. It is typically detected at an advanced stage, at which the therapeutic options are very limited. One remarkable feature of PDAC that contributes to its resilience to treatment is the extreme stromal activation seen in these tumors. Often, the vast majority of tumor bulk consists of non-tumor cells that together provide a tumor-promoting environment. One of the signals that maintains and activates the stroma is the developmental protein Sonic Hedgehog (SHH). As the disease progresses, tumor cells produce increasing amounts of SHH, which activates the surrounding stroma to aid in tumor progression. To better understand this response and identify targets for inhibition, we aimed to elucidate the proteins that mediate the SHH-driven stromal response in PDAC. For this a novel mixed-species coculture model was set up in which the cancer cells are human, and the stroma is modeled by mouse fibroblasts. In conjunction with next-generation sequencing we were able to use the sequence difference between these species to genetically distinguish between the epithelial and stromal responses to SHH. The stromal SHH-dependent genes from this analysis were validated and their relevance for human disease was subsequently determined in two independent patient cohorts. In non-microdissected tissue from PDAC patients, in which a large amount of stroma is present, the targets were confirmed to associate with tumor stroma versus normal pancreatic tissue. Patient survival analysis and immunohistochemistry identified CDA, EDIL3, ITGB4, PLAUR and SPOCK1 as SHH-dependent stromal factors that are associated with poor prognosis in PDAC patients. Summarizing, the presented data provide insight into the role of the activated stroma in PDAC, and how SHH acts to mediate this response. In addition, the study has yielded several candidates that are interesting therapeutic targets for a disease for which treatment options are still inadequate.
摘要：
胰腺导管腺癌（PDAC）仍然是最致命的恶性肿瘤之一。它通常在高级阶段被检测到，治疗选择非常有限。PDAC有助于其对治疗的抵抗力的一个显着特征是在这些肿瘤中看到的极端基质激活。通常,绝大多数肿瘤块由共同提供促进肿瘤的环境的非肿瘤细胞组成。维持和激活基质的信号之一是发育蛋白SonicHedgehog（SHH）。随着疾病的进展,肿瘤细胞产生越来越多的SHH，激活周围的基质以帮助肿瘤进展。为了更好地理解这种反应并确定抑制目标，我们旨在阐明在PDAC中介导SHH驱动的基质反应的蛋白质。为此，建立了一种新的混合物种共培养模型，其中癌细胞是人类的，基质由小鼠成纤维细胞建模。结合下一代测序，我们能够使用这些物种之间的序列差异来遗传区分对SHH的上皮和基质反应。验证了来自该分析的基质SHH依赖性基因，随后在两个独立的患者队列中确定了它们与人类疾病的相关性。在PDAC患者的非微解剖组织中，其中存在大量基质，与正常胰腺组织相比,这些目标被证实与肿瘤间质相关.患者生存分析和免疫组织化学鉴定CDA，EDIL3、ITGB4、PLAUR和SPOCK1是SHH依赖性基质因子，与PDAC患者的不良预后相关。总结，所提供的数据提供了对活化基质在PDAC中的作用的洞察，以及SHH如何调解这一反应。此外,这项研究已经获得了一些候选物,这些候选物对于治疗方案仍然不足的疾病来说是有意义的治疗靶点.
