Disruption of cellular plasticity by repeat RNAs in human pancreatic cancer

Eunae You¹, Patrick Danaher², Chenyue Lu³, Siyu Sun⁴, Luli Zou⁵, Ildiko E Phillips¹, Alexandra S Rojas¹, Natalie I Ho¹, Yuhui Song¹, Michael J Raabe¹, Katherine H Xu¹, Peter M Richieri¹, Hao Li⁴, Natalie Aston¹, Rebecca L Porter⁶, Bidish K Patel¹, Linda T Nieman¹, Nathan Schurman², Briana M Hudson², Khrystyna North², Sarah E Church², Vikram Deshpande⁷, Andrew S Liss⁸, Tae K Kim², Yi Cui², Youngmi Kim², Benjamin D Greenbaum⁹, Martin J Aryee¹⁰, David T Ting¹¹

Affiliations

¹ Mass General Cancer Center, Harvard Medical School, Charlestown, MA 02129, USA.
² NanoString Technologies, Seattle, WA 98109, USA.
³ Mass General Cancer Center, Harvard Medical School, Charlestown, MA 02129, USA; Department of Data Science, Dana-Farber Cancer Institute, Boston, MA 02215, USA.
⁴ Computational Oncology, Department of Epidemiology and Biostatistics, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA.
⁵ Department of Data Science, Dana-Farber Cancer Institute, Boston, MA 02215, USA; Department of Biostatistics, Harvard T.H. Chan School of Public Health, Boston, MA 02115, USA; Broad Institute of Harvard and MIT, Cambridge, MA 02142, USA.
⁶ Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02215, USA.
⁷ Mass General Cancer Center, Harvard Medical School, Charlestown, MA 02129, USA; Department of Pathology, Massachusetts General Hospital, Harvard Medical School, Boston, MA 02114, USA.
⁸ Department of Surgery, Massachusetts General Hospital, Boston, MA 02114, USA.
⁹ Computational Oncology, Department of Epidemiology and Biostatistics, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA; Physiology, Biophysics & Systems Biology, Weill Cornell Medicine, Weill Cornell Medical College, New York, NY 10065, USA.
¹⁰ Department of Data Science, Dana-Farber Cancer Institute, Boston, MA 02215, USA; Department of Biostatistics, Harvard T.H. Chan School of Public Health, Boston, MA 02115, USA; Broad Institute of Harvard and MIT, Cambridge, MA 02142, USA. Electronic address: martin.aryee@ds.dfci.harvard.edu.
¹¹ Mass General Cancer Center, Harvard Medical School, Charlestown, MA 02129, USA; Department of Medicine, Massachusetts General Hospital, Harvard Medical School, Boston, MA 02114, USA. Electronic address: dting1@mgh.harvard.edu.

PMID: 39383862
PMCID: PMC11645244 (available on 2025-12-12)
DOI: 10.1016/j.cell.2024.09.024

Disruption of cellular plasticity by repeat RNAs in human pancreatic cancer

Eunae You et al. Cell. 2024.

. 2024 Dec 12;187(25):7232-7247.e23.

doi: 10.1016/j.cell.2024.09.024. Epub 2024 Oct 8.

Authors

Affiliations

¹ Mass General Cancer Center, Harvard Medical School, Charlestown, MA 02129, USA.
² NanoString Technologies, Seattle, WA 98109, USA.
³ Mass General Cancer Center, Harvard Medical School, Charlestown, MA 02129, USA; Department of Data Science, Dana-Farber Cancer Institute, Boston, MA 02215, USA.
⁴ Computational Oncology, Department of Epidemiology and Biostatistics, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA.
⁵ Department of Data Science, Dana-Farber Cancer Institute, Boston, MA 02215, USA; Department of Biostatistics, Harvard T.H. Chan School of Public Health, Boston, MA 02115, USA; Broad Institute of Harvard and MIT, Cambridge, MA 02142, USA.
⁶ Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02215, USA.
⁷ Mass General Cancer Center, Harvard Medical School, Charlestown, MA 02129, USA; Department of Pathology, Massachusetts General Hospital, Harvard Medical School, Boston, MA 02114, USA.
⁸ Department of Surgery, Massachusetts General Hospital, Boston, MA 02114, USA.
⁹ Computational Oncology, Department of Epidemiology and Biostatistics, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA; Physiology, Biophysics & Systems Biology, Weill Cornell Medicine, Weill Cornell Medical College, New York, NY 10065, USA.
¹⁰ Department of Data Science, Dana-Farber Cancer Institute, Boston, MA 02215, USA; Department of Biostatistics, Harvard T.H. Chan School of Public Health, Boston, MA 02115, USA; Broad Institute of Harvard and MIT, Cambridge, MA 02142, USA. Electronic address: martin.aryee@ds.dfci.harvard.edu.
¹¹ Mass General Cancer Center, Harvard Medical School, Charlestown, MA 02129, USA; Department of Medicine, Massachusetts General Hospital, Harvard Medical School, Boston, MA 02114, USA. Electronic address: dting1@mgh.harvard.edu.

PMID: 39383862
PMCID: PMC11645244 (available on 2025-12-12)
DOI: 10.1016/j.cell.2024.09.024

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.

Keywords: cancer-associated fibroblast; cellular plasticity; extracellular vesicles; pancreatic cancer; repeat RNA; spatial transcriptomics; tumor microenvironment.

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Conflict of interest statement

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.

References

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Disruption of cellular plasticity by repeat RNAs in human pancreatic cancer

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Disruption of cellular plasticity by repeat RNAs in human pancreatic cancer

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