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Cancer Cell-Derived Matrisome Proteins Promote Metastasis in Pancreatic Ductal Adenocarcinoma.
Cancer Research ( IF 11.2 ) Pub Date : 2020-04-01 , DOI: 10.1158/0008-5472.can-19-2578
Chenxi Tian 1 , Daniel Öhlund 2, 3, 4 , Steffen Rickelt 1 , Tommy Lidström 3, 4 , Ying Huang 1 , Liangliang Hao 1 , Renee T Zhao 1 , Oskar Franklin 5 , Sangeeta N Bhatia 1, 6 , David A Tuveson 2 , Richard O Hynes 1, 6
Affiliation  

The prognosis for pancreatic ductal adenocarcinoma (PDAC) remains poor despite decades of effort. The abundant extracellular matrix (ECM) in PDAC comprises a major fraction of the tumor mass and plays various roles in promoting resistance to therapies. However, nonselective depletion of ECM has led to poor patient outcomes. Consistent with that observation, we previously showed that individual matrisome proteins derived from stromal cells correlate with either long or short patient survival. In marked contrast, those derived from cancer cells correlate strongly with poor survival. Here, we studied three cancer cell-derived matrisome proteins that are significantly overrepresented during PDAC progression, AGRN (agrin), SERPINB5 (serine protease inhibitor B5), and CSTB (cystatin B). Using both overexpression and knockdown experiments, we demonstrate that all three are promoters of PDAC metastasis. Furthermore, these proteins operate at different metastatic steps. AGRN promoted epithelial-to-mesenchymal transition in primary tumors, whereas SERPINB5 and CSTB enhanced late steps in the metastatic cascade by elevating invadopodia formation and in vivo extravasation. All three genes were associated with a poor prognosis in human patients and high levels of SERPINB5, secreted by cancer cells and deposited in the ECM, correlated with poor patient prognosis. This study provides strong evidence that cancer cell-derived matrisome proteins can be causal in promoting tumorigenesis and metastasis and lead to poor patient survival. Therefore, compared with the bulk matrix, mostly made by stromal cells, precise interventions targeting cancer cell-derived matrisome proteins, such as AGRN, SERPINB5, and CSTB, may represent preferred potential therapeutic targets. SIGNIFICANCE: This study provides insights into the biological roles of cancer cell-derived matrisome proteins in PDAC and supports the notion that these proteins are protumorigenic and better therapeutic targets.

中文翻译:

癌细胞衍生的基质蛋白促进胰腺导管腺癌的转移。

尽管经过数十年的努力,胰腺导管腺癌 (PDAC) 的预后仍然很差。PDAC 中丰富的细胞外基质 (ECM) 占肿瘤块的主要部分,并在促进对治疗的抗性方面发挥着各种作用。然而,非选择性消耗 ECM 导致患者预后不佳。与该观察结果一致,我们之前表明,源自基质细胞的个体基质体蛋白与患者存活时间的长短相关。与此形成鲜明对比的是,那些源自癌细胞的细胞与较差的存活率密切相关。在这里,我们研究了在 PDAC 进展过程中显着过度表达的三种癌细胞衍生的基质体蛋白,AGRN(集聚蛋白)、SERPINB5(丝氨酸蛋白酶抑制剂 B5)和 CSTB(胱抑素 B)。使用过表达和敲低实验,我们证明这三个都是 PDAC 转移的启动子。此外,这些蛋白质在不同的转移步骤中起作用。AGRN 促进原发性肿瘤中的上皮-间质转化,而 SERPINB5 和 CSTB 通过增加侵袭伪足的形成和体内外渗来增强转移级联反应的晚期步骤。所有三个基因都与人类患者的不良预后相关,而高水平的 SERPINB5(由癌细胞分泌并沉积在 ECM 中)与患者预后不良相关。这项研究提供了强有力的证据,表明癌细胞衍生的基质蛋白可能是促进肿瘤发生和转移并导致患者生存率低的原因。因此,与主要由基质细胞制成的大块基质相比,针对癌细胞衍生的基质体蛋白(如 AGRN、SERPINB5 和 CSTB 可能代表了首选的潜在治疗靶点。意义:这项研究提供了对癌细胞衍生基质蛋白在 PDAC 中的生物学作用的见解,并支持这些蛋白质是促肿瘤发生和更好的治疗靶点的观点。
更新日期:2020-04-03
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