Single Cell Transcriptomics of Pancreatic Cancer Precursors Demonstrates Epithelial and Microenvironmental Heterogeneity as an Early Event in Neoplastic Progression
F Anthony San Lucas,
Feven C. Mulu,
Bret M. Stephens,
Paola A. Guerrero,
Paul A Scheet,
Cullen M. Taniguchi,
Michael P. Kim,
Matthew H Katz,
Aatur D Singhi,
Hector A Alvarez
Posted 26 Apr 2018
bioRxiv DOI: 10.1101/306134 (published DOI: 10.1158/1078-0432.ccr-18-1955)
Posted 26 Apr 2018
Background: Early detection of pancreatic ductal adenocarcinoma (PDAC) remains elusive. Cystic 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. Methods: Single cell RNA sequencing was performed through droplet-based sequencing on 5,403 cells derived from two low grade IPMNs (LGD-IPMN), two high grade IPMNs (HGD-IPMN), and two PDACs (all surgically resected). Results: Analysis of single cell transcriptomes revealed heterogeneous alterations within both the epithelium and in the tumor microenvironment during the progression of non-invasive dysplasia to invasive cancer. Specifically, while HGD-IPMNs expressed many core-signaling pathways described in PDAC, even 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. Conclusions: This study demonstrates the ability to perform high resolution profiling of the transcriptomic changes that occur during the 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.
- Downloaded 1,274 times
- Download rankings, all-time:
- Site-wide: 12,572
- In pathology: 57
- Year to date:
- Site-wide: None
- Since beginning of last month:
- Site-wide: 50,568
Downloads over time
Distribution of downloads per paper, site-wide
- 27 Nov 2020: The website and API now include results pulled from medRxiv as well as bioRxiv.
- 18 Dec 2019: We're pleased to announce PanLingua, a new tool that enables you to search for machine-translated bioRxiv preprints using more than 100 different languages.
- 21 May 2019: PLOS Biology has published a community page about Rxivist.org and its design.
- 10 May 2019: The paper analyzing the Rxivist dataset has been published at eLife.
- 1 Mar 2019: We now have summary statistics about bioRxiv downloads and submissions.
- 8 Feb 2019: Data from Altmetric is now available on the Rxivist details page for every preprint. Look for the "donut" under the download metrics.
- 30 Jan 2019: preLights has featured the Rxivist preprint and written about our findings.
- 22 Jan 2019: Nature just published an article about Rxivist and our data.
- 13 Jan 2019: The Rxivist preprint is live!