Veenstra Veronique L, Damhofer Helene, Waasdorp Cynthia, Steins Anne, Kocher Hemant M, Medema Jan P, van Laarhoven Hanneke W, Bijlsma Maarten F
Laboratory for Experimental Oncology and Radiobiology, Center for Experimental and Molecular Medicine, Academic Medical Center and Cancer Center Amsterdam, The Netherlands.
Centre for Tumour Biology, Barts Cancer Institute, Queen Mary University of London, UK.
Mol Oncol. 2017 Aug;11(8):1050-1064. doi: 10.1002/1878-0261.12073. Epub 2017 Jun 5.
Pancreatic ductal adenocarcinoma (PDAC) is marked by an abundant stromal deposition. This stroma is suspected to harbor both tumor-promoting and tumor-suppressing properties. This is underscored by the disappointing results of stroma targeting in clinical studies. Given the complexity of tumor-stroma interaction in PDAC, there is a need to identify the stromal proteins that are predominantly tumor-promoting. One possible candidate is SPOCK1 that we previously identified in a screening effort in PDAC. We extensively mined PDAC gene expression datasets, and used species-specific transcript analysis in mixed-species models for PDAC to study the patterns and driver mechanisms of SPOCK1 expression in PDAC. Advanced organotypic coculture models with primary patient-derived tumor cells were used to further characterize the function of this protein. We found SPOCK1 expression to be predominantly stromal. Expression of SPOCK1 was associated with poor disease outcome. Coculture and ligand stimulation experiments revealed that SPOCK1 is expressed in response to tumor cell-derived transforming growth factor-beta. Functional assessment in cocultures demonstrated that SPOCK1 strongly affects the composition of the extracellular collagen matrix and by doing so, enables invasive tumor cell growth in PDAC. By defining the expression pattern and functional properties of SPOCK1 in pancreatic cancer, we have identified a stromal mediator of extracellular matrix remodeling that indirectly affects the aggressive behavior of PDAC cells. The recognition that stromal proteins actively contribute to the protumorigenic remodeling of the tumor microenvironment should aid the design of future clinical studies to target specific stromal targets.
胰腺导管腺癌（PDAC）的特征是大量的间质沉积。这种间质被怀疑同时具有促进肿瘤和抑制肿瘤的特性。临床研究中针对间质的治疗结果令人失望，这突出了这一点。鉴于PDAC中肿瘤-间质相互作用的复杂性，有必要确定主要促进肿瘤的间质蛋白。一个可能的候选蛋白是SPOCK1，我们之前在对PDAC的一项筛选研究中鉴定出了它。我们广泛挖掘了PDAC基因表达数据集，并在PDAC的混合物种模型中使用物种特异性转录分析来研究SPOCK1在PDAC中的表达模式和驱动机制。使用来自原发性患者肿瘤细胞的先进器官型共培养模型进一步表征该蛋白的功能。我们发现SPOCK1的表达主要存在于间质中。SPOCK1的表达与不良疾病预后相关。共培养和配体刺激实验表明，SPOCK1是响应肿瘤细胞衍生的转化生长因子-β而表达的。共培养中的功能评估表明，SPOCK1强烈影响细胞外胶原基质的组成，从而使PDAC中的肿瘤细胞能够侵袭性生长。通过定义SPOCK1在胰腺癌中的表达模式和功能特性，我们确定了一种细胞外基质重塑的间质介质，它间接影响PDAC细胞的侵袭行为。认识到间质蛋白积极参与肿瘤微环境的促肿瘤重塑，应该有助于未来针对特定间质靶点的临床研究设计。
