1. Disruption of cellular plasticity by repeat RNAs in human pancreatic cancer.
- Author
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You E, Danaher P, Lu C, Sun S, Zou L, Phillips IE, Rojas AS, Ho NI, Song Y, Raabe MJ, Xu KH, Richieri PM, Li H, Aston N, Porter RL, Patel BK, Nieman LT, Schurman N, Hudson BM, North K, Church SE, Deshpande V, Liss AS, Kim TK, Cui Y, Kim Y, Greenbaum BD, Aryee MJ, and Ting DT
- Subjects
- Humans, Cancer-Associated Fibroblasts metabolism, Interferon Regulatory Factor-3 metabolism, Extracellular Vesicles metabolism, Cell Line, Tumor, Gene Expression Regulation, Neoplastic, Signal Transduction, Myofibroblasts metabolism, Immunity, Innate, RNA metabolism, Pancreatic Neoplasms genetics, Pancreatic Neoplasms pathology, Pancreatic Neoplasms metabolism, Carcinoma, Pancreatic Ductal genetics, Carcinoma, Pancreatic Ductal pathology, Carcinoma, Pancreatic Ductal metabolism, Cell Plasticity, Tumor Microenvironment
- 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., Competing Interests: Declaration of interests D.T.T. and B.D.G. are co-founders with equity and consulting fees from ROME Therapeutics, a company developing drugs targeting repetitive elements, but this work was not supported by ROME Therapeutics. D.T.T. received in kind research support and a speaking honorarium from NanoString Technologies, and in kind research support from ACD-Biotechne, which was used in this work. M.J.A. is a co-founder of, owns equity in, and receives consulting fees from SeQure Dx, unrelated to this work. M.J.A. receives consulting fees from Chroma Medicine, unrelated to this work. P.D., N.S., B.M.H., K.N., S.E.C., T.K.K., Y.C., and Y.K. are or were employees of NanoString Technologies. D.T.T. has received consulting fees from PanTher Therapeutics, AstraZeneca, Sonata Therapeutics, Moderna, abrdn, Astellas, and Leica Biosystems Imaging; is a founder and has equity in PanTher Therapeutics and TellBio, Inc.; and is on the scientific advisory board with equity for ImproveBio, Inc., which are not related to this work. D.T.T. receives research support from Sanofi, AVA LifeScience GmbH, and Incyte, which was not used in this work. B.D.G. is a consultant or received honoraria for Darwin Health, Merck, PMV Pharma, Merck, Bristol-Meyers Squibb, and Chugai Pharmaceuticals and has research funding from Bristol-Meyers Squibb., (Copyright © 2024 Elsevier Inc. All rights reserved.)
- Published
- 2024
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