Single-cell transcriptomes of pancreatic preinvasive lesions and cancer reveal acinar metaplastic cells’ heterogeneity

Yehuda Schlesinger, Oshri Yosefov-Levi, Dror Kolodkin-Gal, Roy Zvi Granit, Luriano Peters, Rachel Kalifa, Lei Xia, Abdelmajeed Nasereddin, Idit Shiff, Osher Amran, Yuval Nevo, Sharona Elgavish, Karine Atlan, Gideon Zamir, Oren Parnas*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

98 Scopus citations

Abstract

Acinar metaplasia is an initial step in a series of events that can lead to pancreatic cancer. Here we perform single-cell RNA-sequencing of mouse pancreas during the progression from preinvasive stages to tumor formation. Using a reporter gene, we identify metaplastic cells that originated from acinar cells and express two transcription factors, Onecut2 and Foxq1. Further analyses of metaplastic acinar cell heterogeneity define six acinar metaplastic cell types and states, including stomach-specific cell types. Localization of metaplastic cell types and mixture of different metaplastic cell types in the same pre-malignant lesion is shown. Finally, single-cell transcriptome analyses of tumor-associated stromal, immune, endothelial and fibroblast cells identify signals that may support tumor development, as well as the recruitment and education of immune cells. Our findings are consistent with the early, premalignant formation of an immunosuppressive environment mediated by interactions between acinar metaplastic cells and other cells in the microenvironment.

Original languageAmerican English
Article number4516
JournalNature Communications
Volume11
Issue number1
DOIs
StatePublished - 1 Dec 2020

Bibliographical note

Funding Information:
We would like to thank Dr. Yuval Dor, Dr. Eli Pikarski, Dr. Zvika Granot and Dr. Ittai Ben-Porath for fruitful discussions and advice. We thank all members of the Parnas lab, Dr. Gillian Kay for English editing, Dr. Sharona Tornovsky-Babeay, Dr. Ilan Stein, Nofar Rozenberg and Yelena Piontek and Housam Husseini for expertize and support with IHC. Dr. Zakhariya Manevitch, for the tutorial and support in the microscopy unit, Dr. Eleonora Medvedev cell sorting and Shaul Horwitz mice holding. This project has received funding from the European Research Council (ERC) under the European Union’s Horizon 2020 Research and Innovation program (grant agreement No. 758735 O.P.), Israel Science Foundation—Broad Institute Joint Program (grant No. 2621/18 O.P.), Israel Science Foundation grant (No. 526/18 O.P.), the Alex U. Soyka Program and grants from the Israel Cancer Research Fund (ICRF), Project Grant (G.Z.).

Publisher Copyright:
© 2020, The Author(s).

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