Morphology-guided transcriptomic analysis of human pancreatic cancer organoids reveals microenvironmental signals that enhance invasion.
Morphology-guided transcriptomic analysis of human pancreatic cancer organoids reveals microenvironmental signals that enhance invasion.
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人胰腺癌器官的形态指导的转录组分析揭示了增强侵袭的微环境信号。
DOI：
10.1172/jci162054
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发表时间：
2023-04-17
影响因子：
15.9
通讯作者：
Wood, Laura D.
中科院分区：
文献类型：
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作者：
Jeong, Yea Ji;Knutsdottir, Hildur;Shojaeian, Fatemeh;Lerner, Michael G.;Wissler, Maria F.;Henriet, Elodie;Ng, Tammy;Datta, Shalini;Navarro-Serer, Bernat;Chianchiano, Peter;Kinny-Koester, Benedict;Zimmerman, Jacquelyn W.;Stein-O'Brien, Genevieve;Gaida, Matthias M.;Eshleman, James R.;Lin, Ming-Tseh;Fertig, Elana J.;Ewald, Andrew J.;Bader, Joel S.;Wood, Laura D.
胰腺导管腺癌(PDAC)常伴有转移，但人PDAC细胞中驱动侵袭的分子程序尚不清楚。使用基于侵袭表型的PDAC有机化合物分离和收集的实验管道，我们在我们的有机物模型中评估了与侵袭相关的转录程序。我们鉴定了侵袭性器官与来自同一患者的匹配的非侵袭性器官中差异表达的基因，并证实编码的蛋白质在器质性侵袭性突起中增强。我们在入侵类器官中发现了3个不同的转录群，其中2个与形态入侵模式直接相关，并具有不同的上调途径。利用公开的单细胞RNA测序数据，我们将我们的转录组映射到人类PDAC组织样本上，突出了转录组之间肿瘤微环境的差异，并表明肿瘤微环境中的非肿瘤细胞可以调节肿瘤细胞的侵袭。为了进一步解决这种可能性，我们进行了计算配体-受体分析，并验证了多个配体(转化生长因子-β1、IL-6、CXCL12、MMP9)对新鲜人类PDAC有机化合物的侵袭和基因表达的影响。我们的结果确定了驱动形态定义的侵袭模式的分子程序，并强调肿瘤微环境是这些程序的潜在调节器。
Pancreatic ductal adenocarcinoma (PDAC) frequently presents with metastasis, but the molecular programs in human PDAC cells that drive invasion are not well understood. Using an experimental pipeline enabling PDAC organoid isolation and collection based on invasive phenotype, we assessed the transcriptomic programs associated with invasion in our organoid model. We identified differentially expressed genes in invasive organoids compared with matched noninvasive organoids from the same patients, and we confirmed that the encoded proteins were enhanced in organoid invasive protrusions. We identified 3 distinct transcriptomic groups in invasive organoids, 2 of which correlated directly with the morphological invasion patterns and were characterized by distinct upregulated pathways. Leveraging publicly available single-cell RNA-sequencing data, we mapped our transcriptomic groups onto human PDAC tissue samples, highlighting differences in the tumor microenvironment between transcriptomic groups and suggesting that non-neoplastic cells in the tumor microenvironment can modulate tumor cell invasion. To further address this possibility, we performed computational ligand-receptor analysis and validated the impact of multiple ligands (TGF-β1, IL-6, CXCL12, MMP9) on invasion and gene expression in an independent cohort of fresh human PDAC organoids. Our results identify molecular programs driving morphologically defined invasion patterns and highlight the tumor microenvironment as a potential modulator of these programs.