한빛사논문
Eunae You,1 Patrick Danaher,2 Chenyue Lu,1,3 Siyu Sun,4 Luli Zou,3,5,6 Ildiko E. Phillips,1 Alexandra S. Rojas,1 Natalie I. Ho,1 Yuhui Song,1 Michael J. Raabe,1 Katherine H. Xu,1 Peter M. Richieri,1 Hao Li,4 Natalie Aston,1 Rebecca L. Porter,7 Bidish K. Patel,1 Linda T. Nieman,1 Nathan Schurman,2 Briana M. Hudson,2 Khrystyna North,2 Sarah E. Church,2 Vikram Deshpande,1,8 Andrew S. Liss,9 Tae K. Kim,2 Yi Cui,2 Youngmi Kim,2 Benjamin D. Greenbaum,4,10 Martin J. Aryee,3,5,6,12,* and David T. Ting 1,11,12,13,*
1Mass General Cancer Center, Harvard Medical School, Charlestown, MA 02129, USA
2NanoString Technologies, Seattle, WA 98109, USA
3Department of Data Science, Dana-Farber Cancer Institute, Boston, MA 02215, USA
4Computational Oncology, Department of Epidemiology and Biostatistics, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA
5Department of Biostatistics, Harvard T.H. Chan School of Public Health, Boston, MA 02115, USA
6Broad Institute of Harvard and MIT, Cambridge, MA 02142, USA
7Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02215, USA
8Department of Pathology, Massachusetts General Hospital, Harvard Medical School, Boston, MA 02114, USA
9Department of Surgery, Massachusetts General Hospital, Boston, MA 02114, USA
10Physiology, Biophysics & Systems Biology, Weill Cornell Medicine, Weill Cornell Medical College, New York, NY 10065, USA
11Department of Medicine, Massachusetts General Hospital, Harvard Medical School, Boston, MA 02114, USA
12These authors contributed equally
13Lead contact
*Corresponding authors: correspondence to Martin J. Aryee or David T. Ting
Abstract
Aberrant expression of repeat RNAs in pancreatic ductal adenocarcinoma (PDAC) mimics viral-like responses with implications on tumor cell state and the response of the surrounding microenvironment. To better understand the relationship of repeat RNAs in human PDAC, we performed spatial molecular imaging at single-cell resolution in 46 primary tumors, revealing correlations of high repeat RNA expression with alterations in epithelial state in PDAC cells and myofibroblast phenotype in cancer-associated fibroblasts (CAFs). This loss of cellular identity is observed with dosing of extracellular vesicles (EVs) and individual repeat RNAs of PDAC and CAF cell culture models pointing to cell-cell intercommunication of these viral-like elements. Differences in PDAC and CAF responses are driven by distinct innate immune signaling through interferon regulatory factor 3 (IRF3). The cell-context-specific viral-like responses to repeat RNAs provide a mechanism for modulation of cellular plasticity in diverse cell types in the PDAC microenvironment.
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