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Epigenetic reprogramming shapes the cellular landscape of schwannoma

Authors :
S. John Liu
Tim Casey-Clyde
Nam Woo Cho
Jason Swinderman
Melike Pekmezci
Mark C. Dougherty
Kyla Foster
William C. Chen
Javier E. Villanueva-Meyer
Danielle L. Swaney
Harish N. Vasudevan
Abrar Choudhury
Jonathan D. Breshears
Ursula E. Lang
Charlotte D Eaton
Kamir J. Hiam-Galvez
Erica Stevenson
Kuei-Ho Chen
Brian V. Lien
David Wu
Steve E. Braunstein
Penny K. Sneed
Stephen T. Magill
Daniel Lim
Michael W. McDermott
Mitchel S. Berger
Arie Perry
Nevan J. Krogan
Marlon Hansen
Matthew H. Spitzer
Luke Gilbert
Philip V. Theodosopoulos
David R. Raleigh
Publication Year :
2022
Publisher :
Cold Spring Harbor Laboratory, 2022.

Abstract

SummaryCell state evolution underlies tumor development and response to therapy1, but mechanisms specifying cancer cell states and intratumor heterogeneity are incompletely understood. Schwannomas are the most common tumors of the peripheral nervous system and are treated with surgery and ionizing radiation2–5. Schwannomas can oscillate in size for many years after radiotherapy6,7, suggesting treatment may reprogram schwannoma cells or the tumor microenvironment. Here we show epigenetic reprogramming shapes the cellular landscape of schwannomas. We find schwannomas are comprised of 2 molecular groups distinguished by reactivation of neural crest development pathways or misactivation of nerve injury mechanisms that specify cancer cell states and the architecture of the tumor immune microenvironment. Schwannoma molecular groups can arise independently, but ionizing radiation is sufficient for epigenetic reprogramming of neural crest to immune-enriched schwannoma by remodeling chromatin accessibility, gene expression, and metabolism to drive schwannoma cell state evolution and immune cell infiltration. To define functional genomic mechanisms underlying epigenetic reprograming of schwannomas, we develop a technique for simultaneous interrogation of chromatin accessibility and gene expression coupled with genetic and therapeutic perturbations in single-nuclei. Our results elucidate a framework for understanding epigenetic drivers of cancer evolution and establish a paradigm of epigenetic reprograming of cancer in response to radiotherapy.

Details

Database :
OpenAIRE
Accession number :
edsair.doi...........cc6f1b4185d7958479e36fb130929ae6
Full Text :
https://doi.org/10.1101/2022.12.23.521842