Department of Translational Molecular Pathology, The University of Texas MD Anderson Cancer Center, Houston, Texas.
The University of Texas MD Anderson Cancer Center UTHealth Graduate School of Biomedical Sciences, Houston, Texas.
Clin Cancer Res. 2019 Apr 1;25(7):2194-2205. doi: 10.1158/1078-0432.CCR-18-1955. Epub 2018 Nov 1.
Early detection of pancreatic ductal adenocarcinoma (PDAC) remains elusive. Precursor lesions of PDAC, specifically intraductal papillary mucinous neoplasms (IPMNs), represent a 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 heterogeneities that accompany multistep progression from noninvasive IPMNs to PDAC.
Single-cell RNA sequencing was performed through droplet-based sequencing on 5,403 cells from 2 low-grade IPMNs (LGD-IPMNs), 2 high-grade IPMNs (HGD-IPMN), and 2 PDACs (all surgically resected).
Analysis of single-cell transcriptomes revealed heterogeneous alterations within the epithelium and the tumor microenvironment during the progression of noninvasive dysplasia to invasive cancer. Although 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 proinflammatory immune component was readily seen in low-grade IPMNs, composed 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 heterogeneities that accompany early cancer pathogenesis and might be a useful substrate to identify targets for cancer interception..
胰腺导管腺癌 (PDAC) 的早期检测仍然难以实现。PDAC 的前驱病变，特别是导管内乳头状黏液性肿瘤 (IPMNs)，代表了向浸润性肿瘤发展的途径，尽管进展的分子相关性仍有待充分阐明。单细胞转录组学为剖析从非浸润性 IPMN 到 PDAC 的多步进展过程中伴随的上皮和微环境异质性提供了独特的途径。
通过基于液滴的测序对 2 个低级别 IPMN（LGD-IPMN）、2 个高级别 IPMN（HGD-IPMN）和 2 个 PDAC（均通过手术切除）中的 5403 个细胞进行单细胞 RNA 测序。
单细胞转录组分析显示，在非浸润性发育不良向浸润性癌症进展过程中，上皮和肿瘤微环境中存在异质性改变。虽然 HGD-IPMN 表达了 PDAC 中描述的许多核心信号通路，但 LGD-IPMN 则存在与浸润性癌症重叠的具有转录组特征的单细胞亚群。值得注意的是，在低级别 IPMN 中很容易看到促炎免疫成分，由细胞毒性 T 细胞、活化的辅助性 T 细胞和树突状细胞组成，在肿瘤进展过程中逐渐耗尽，同时伴有髓系来源的抑制细胞浸润。最后，基质成纤维细胞群体是异质的，并在浸润性癌发生过程中获得了先前描述的促进肿瘤和逃避免疫的表型。
本研究证明了对囊性 PDAC 前体多步进展过程中发生的转录组变化进行高分辨率分析的能力。值得注意的是，单细胞分析为早期癌症发病机制伴随的上皮和微环境异质性提供了无与伦比的见解，并且可能是识别癌症干预目标的有用基质。
