Single-Cell Transcriptomics of Pancreatic Cancer Precursors Demonstrates Epithelial and Microenvironmental Heterogeneity as an Early Event in Neoplastic Progression.
Single-Cell Transcriptomics of Pancreatic Cancer Precursors Demonstrates Epithelial and Microenvironmental Heterogeneity as an Early Event in Neoplastic Progression.
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DOI：
10.1158/1078-0432.ccr-18-1955
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发表时间：
2019-04-01
期刊：
影响因子：
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通讯作者：
Alvarez HA
中科院分区：
文献类型：
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作者：
Bernard V;Semaan A;Huang J;San Lucas FA;Mulu FC;Stephens BM;Guerrero PA;Huang Y;Zhao J;Kamyabi N;Sen S;Scheet PA;Taniguchi CM;Kim MP;Tzeng CW;Katz MH;Singhi AD;Maitra A;Alvarez HA
胰腺导管腺癌（PDAC）的早期检测仍然是难以捉摸的。PDAC的前驱病变，特别是导管内乳头状粘液性肿瘤（IPMN）代表了一个真正的途径，浸润性肿瘤，虽然进展的分子相关性仍有待充分阐明。单细胞转录组学提供了一个独特的途径解剖上皮和微环境的异质性，伴随着从非侵入性IPMNs到PDAC的多步进展。通过基于液滴的测序对来自两个低级IPMN（LGD-IPMN）、两个高级IPMN（HGD-IPMN）和两个PDAC（均手术切除）的5，403个细胞进行单细胞RNA测序。单细胞转录组的分析揭示了在非侵袭性异型增生进展为侵袭性癌症期间上皮和肿瘤微环境内的异质性改变。虽然HGD-IPMNs表达了PDAC中描述的许多核心信号传导途径，但LGD-IPMNs包含具有与侵袭性癌症重叠的转录组学特征的单细胞亚群。值得注意的是，促炎性免疫组分在低级IPMN中很容易观察到，其由细胞毒性T细胞、活化的T辅助细胞和树突状细胞组成，其在肿瘤进展期间逐渐耗尽，伴随着髓源性抑制细胞的浸润。最后，间质肌成纤维细胞群体是异质性的，并获得了先前描述的肿瘤促进和免疫逃避表型在侵袭性癌变。这项研究证明了对囊性PDAC前体向癌症的多步进展期间发生的转录组学变化进行高分辨率分析的能力。值得注意的是，单细胞分析提供了一个无与伦比的洞察上皮和微环境的异质性，伴随着早期癌症的发病机制，并可能是一个有用的基板，以确定癌症拦截的目标。
Early detection of pancreatic ductal adenocarcinoma (PDAC) remains elusive. Precursor lesions of PDAC, specifically, intraductal papillary mucinous neoplasms (IPMNs) represent a bona fide pathway to invasive neoplasia, although the molecular correlates of progression remain to be fully elucidated. Single cell transcriptomics provides a unique avenue for dissecting both the epithelial and microenvironmental heterogeneity that accompany multistep progression from non-invasive IPMNs to PDAC. Single cell RNA-sequencing was performed through droplet-based sequencing on 5,403 cells from two low-grade IPMNs (LGD-IPMN), two high-grade IPMNs (HGD-IPMN), and two PDACs (all surgically resected). Analysis of single cell transcriptomes revealed heterogeneous alterations within the epithelium and the tumor microenvironment during the progression of non-invasive dysplasia to invasive cancer. While HGD-IPMNs expressed many core-signaling pathways described in PDAC, LGD-IPMNs harbored subsets of single cells with a transcriptomic profile that overlapped with invasive cancer. Notably, a pro-inflammatory immune component was readily seen in low-grade IPMNs, comprised of cytotoxic T-cells, activated T-helper cells, and dendritic cells, which was progressively depleted during neoplastic progression, accompanied by infiltration of myeloid-derived suppressor cells. Finally, stromal myofibroblast populations were heterogeneous, and acquired a previously described tumor-promoting and immune-evading phenotype during invasive carcinogenesis. This study demonstrates the ability to perform high resolution profiling of the transcriptomic changes that occur during multistep progression of cystic PDAC precursors to cancer. Notably, single cell analysis provides an unparalleled insight into both the epithelial and microenvironmental heterogeneity that accompany early cancer pathogenesis, and might be a useful substrate to identify targets for cancer interception.