Single-Cell Transcriptomics of Pancreatic Cancer Precursors Demonstrates Epithelial and Microenvironmental Heterogeneity as an Early Event in Neoplastic Progression

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...

Ausführliche Beschreibung

Gespeichert in:
Bibliographische Detailangaben
Veröffentlicht in:Clinical cancer research Jg. 25; H. 7; S. 2194
Hauptverfasser: Bernard, Vincent, Semaan, Alexander, Huang, Jonathan, San Lucas, F Anthony, Mulu, Feven C, Stephens, Bret M, Guerrero, Paola A, Huang, Yanqing, Zhao, Jun, Kamyabi, Nabiollah, Sen, Subrata, Scheet, Paul A, Taniguchi, Cullen M, Kim, Michael P, Tzeng, Ching-Wei, Katz, Matthew H, Singhi, Aatur D, Maitra, Anirban, Alvarez, Hector A
Format: Journal Article
Sprache:Englisch
Veröffentlicht: United States 01.04.2019
Schlagworte:
Adenocarcinoma, Mucinous - genetics
Carcinoma, Pancreatic Ductal - genetics
Disease Progression
Humans
Pancreatic Neoplasms - genetics
Phenotype
Tumor Microenvironment
ISSN:1557-3265, 1557-3265
Online-Zugang:Weitere Angaben
Tags: Tag hinzufügen
Keine Tags, Fügen Sie den ersten Tag hinzu!
Beschreibung
Zusammenfassung: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. .
Bibliographie:ObjectType-Article-1
SourceType-Scholarly Journals-1
ObjectType-Feature-2
content type line 23
ISSN:1557-3265
1557-3265
DOI:10.1158/1078-0432.CCR-18-1955