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Stromal Microenvironment Shapes the Intratumoral Architecture of Pancreatic Cancer.
Cell ( IF 45.5 ) Pub Date : 2019-05-30 , DOI: 10.1016/j.cell.2019.05.012 Matteo Ligorio 1 , Srinjoy Sil 2 , Jose Malagon-Lopez 3 , Linda T Nieman 2 , Sandra Misale 2 , Mauro Di Pilato 4 , Richard Y Ebright 2 , Murat N Karabacak 5 , Anupriya S Kulkarni 2 , Ann Liu 2 , Nicole Vincent Jordan 2 , Joseph W Franses 2 , Julia Philipp 2 , Johannes Kreuzer 2 , Niyati Desai 2 , Kshitij S Arora 6 , Mihir Rajurkar 2 , Elad Horwitz 2 , Azfar Neyaz 2 , Eric Tai 2 , Neelima K C Magnus 2 , Kevin D Vo 2 , Chittampalli N Yashaswini 2 , Francesco Marangoni 4 , Myriam Boukhali 2 , Jackson P Fatherree 2 , Leah J Damon 2 , Kristina Xega 2 , Rushil Desai 2 , Melissa Choz 2 , Francesca Bersani 2 , Adam Langenbucher 2 , Vishal Thapar 3 , Robert Morris 2 , Ulrich F Wellner 7 , Oliver Schilling 8 , Michael S Lawrence 2 , Andrew S Liss 9 , Miguel N Rivera 3 , Vikram Deshpande 3 , Cyril H Benes 2 , Shyamala Maheswaran 1 , Daniel A Haber 10 , Carlos Fernandez-Del-Castillo 1 , Cristina R Ferrone 1 , Wilhelm Haas 2 , Martin J Aryee 11 , David T Ting 12
Cell ( IF 45.5 ) Pub Date : 2019-05-30 , DOI: 10.1016/j.cell.2019.05.012 Matteo Ligorio 1 , Srinjoy Sil 2 , Jose Malagon-Lopez 3 , Linda T Nieman 2 , Sandra Misale 2 , Mauro Di Pilato 4 , Richard Y Ebright 2 , Murat N Karabacak 5 , Anupriya S Kulkarni 2 , Ann Liu 2 , Nicole Vincent Jordan 2 , Joseph W Franses 2 , Julia Philipp 2 , Johannes Kreuzer 2 , Niyati Desai 2 , Kshitij S Arora 6 , Mihir Rajurkar 2 , Elad Horwitz 2 , Azfar Neyaz 2 , Eric Tai 2 , Neelima K C Magnus 2 , Kevin D Vo 2 , Chittampalli N Yashaswini 2 , Francesco Marangoni 4 , Myriam Boukhali 2 , Jackson P Fatherree 2 , Leah J Damon 2 , Kristina Xega 2 , Rushil Desai 2 , Melissa Choz 2 , Francesca Bersani 2 , Adam Langenbucher 2 , Vishal Thapar 3 , Robert Morris 2 , Ulrich F Wellner 7 , Oliver Schilling 8 , Michael S Lawrence 2 , Andrew S Liss 9 , Miguel N Rivera 3 , Vikram Deshpande 3 , Cyril H Benes 2 , Shyamala Maheswaran 1 , Daniel A Haber 10 , Carlos Fernandez-Del-Castillo 1 , Cristina R Ferrone 1 , Wilhelm Haas 2 , Martin J Aryee 11 , David T Ting 12
Affiliation
Single-cell technologies have described heterogeneity across tissues, but the spatial distribution and forces that drive single-cell phenotypes have not been well defined. Combining single-cell RNA and protein analytics in studying the role of stromal cancer-associated fibroblasts (CAFs) in modulating heterogeneity in pancreatic cancer (pancreatic ductal adenocarcinoma [PDAC]) model systems, we have identified significant single-cell population shifts toward invasive epithelial-to-mesenchymal transition (EMT) and proliferative (PRO) phenotypes linked with mitogen-activated protein kinase (MAPK) and signal transducer and activator of transcription 3 (STAT3) signaling. Using high-content digital imaging of RNA in situ hybridization in 195 PDAC tumors, we quantified these EMT and PRO subpopulations in 319,626 individual cancer cells that can be classified within the context of distinct tumor gland "units." Tumor gland typing provided an additional layer of intratumoral heterogeneity that was associated with differences in stromal abundance and clinical outcomes. This demonstrates the impact of the stroma in shaping tumor architecture by altering inherent patterns of tumor glands in human PDAC.
中文翻译:
基质微环境塑造胰腺癌的瘤内结构。
单细胞技术描述了跨组织的异质性,但驱动单细胞表型的空间分布和力量尚未得到很好的定义。结合单细胞 RNA 和蛋白质分析来研究间质癌相关成纤维细胞 (CAF) 在调节胰腺癌(胰腺导管腺癌 [PDAC])模型系统异质性中的作用,我们发现单细胞群向侵袭性上皮细胞的显着转变间充质转化 (EMT) 和增殖 (PRO) 表型与丝裂原激活蛋白激酶 (MAPK) 以及信号转导子和转录激活子 3 (STAT3) 信号传导相关。利用 195 个 PDAC 肿瘤中 RNA 原位杂交的高内涵数字成像,我们对 319,626 个单个癌细胞中的这些 EMT 和 PRO 亚群进行了量化,这些癌细胞可以在不同的肿瘤腺“单位”的背景下进行分类。肿瘤腺分型提供了额外的肿瘤内异质性,该异质性与基质丰度和临床结果的差异相关。这证明了基质通过改变人类 PDAC 肿瘤腺体的固有模式来塑造肿瘤结构。
更新日期:2019-05-31
中文翻译:
基质微环境塑造胰腺癌的瘤内结构。
单细胞技术描述了跨组织的异质性,但驱动单细胞表型的空间分布和力量尚未得到很好的定义。结合单细胞 RNA 和蛋白质分析来研究间质癌相关成纤维细胞 (CAF) 在调节胰腺癌(胰腺导管腺癌 [PDAC])模型系统异质性中的作用,我们发现单细胞群向侵袭性上皮细胞的显着转变间充质转化 (EMT) 和增殖 (PRO) 表型与丝裂原激活蛋白激酶 (MAPK) 以及信号转导子和转录激活子 3 (STAT3) 信号传导相关。利用 195 个 PDAC 肿瘤中 RNA 原位杂交的高内涵数字成像,我们对 319,626 个单个癌细胞中的这些 EMT 和 PRO 亚群进行了量化,这些癌细胞可以在不同的肿瘤腺“单位”的背景下进行分类。肿瘤腺分型提供了额外的肿瘤内异质性,该异质性与基质丰度和临床结果的差异相关。这证明了基质通过改变人类 PDAC 肿瘤腺体的固有模式来塑造肿瘤结构。