Damhofer Helene, Medema Jan Paul, Veenstra Veronique L, Badea Liviu, Popescu Irinel, Roelink Henk, Bijlsma Maarten F
Laboratory for Experimental Oncology and Radiobiology, Academic Medical Center, University of Amsterdam, Meibergdreef 9, 1105AZ Amsterdam, The Netherlands.
Mol Oncol. 2013 Dec;7(6):1031-42. doi: 10.1016/j.molonc.2013.08.004. Epub 2013 Aug 16.
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.
胰腺导管腺癌（PDAC）仍然是最致命的恶性肿瘤之一。它通常在晚期才被发现，而在这个阶段治疗选择非常有限。PDAC的一个显著特征是这些肿瘤中出现的极端基质激活，这导致其对治疗具有抵抗力。通常，绝大多数肿瘤体积由非肿瘤细胞组成，这些细胞共同提供了一个促进肿瘤生长的环境。维持和激活基质的信号之一是发育蛋白音猬因子（SHH）。随着疾病进展，肿瘤细胞产生越来越多的SHH，激活周围基质以促进肿瘤进展。为了更好地理解这种反应并确定抑制靶点，我们旨在阐明介导PDAC中SHH驱动的基质反应的蛋白质。为此，建立了一种新型的混合物种共培养模型，其中癌细胞是人源的，基质由小鼠成纤维细胞模拟。结合下一代测序，我们能够利用这些物种之间的序列差异从基因上区分上皮和基质对SHH的反应。对该分析中依赖SHH的基质基因进行了验证，并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。在来自PDAC患者的非显微切割组织中（其中存在大量基质），证实这些靶点与肿瘤基质和正常胰腺组织相关。患者生存分析和免疫组织化学确定CDA、EDIL3、ITGB4、PLAUR和SPOCK1为依赖SHH的基质因子，它们与PDAC患者的不良预后相关。总之，所呈现的数据提供了对激活的基质在PDAC中的作用以及SHH如何介导这种反应的见解。此外，该研究还产生了几个有潜力的候选靶点，对于治疗选择仍然不足的这种疾病来说，它们是有趣的治疗靶点。
