TY - UNPB
T1 - Cancer cells co-evolve with retrotransposons to mitigate viral mimicry
AU - Sun, Siyu
AU - Hong, Jungeui
AU - You, Eunae
AU - Tsanov, Kaloyan M
AU - Chacon-Barahona, Jonathan
AU - Gioacchino, Andrea Di
AU - Hoyos, David
AU - Li, Hao
AU - Jiang, Hua
AU - Ly, Han
AU - Marhon, Sajid
AU - Murali, Rajmohan
AU - Chanda, Pharto
AU - Karacay, Ali
AU - Vabret, Nicolas
AU - De Carvalho, Daniel D
AU - LaCava, John
AU - Lowe, Scott W
AU - Ting, David T
AU - Iacobuzio-Donahue, Christine A
AU - Solovyov, Alexander
AU - Greenbaum, Benjamin D
PY - 2023/5/20
Y1 - 2023/5/20
N2 - Overexpression of repetitive elements is an emerging hallmark of human cancers [1]. Diverse repeats can mimic viruses by replicating within the cancer genome through retrotransposition, or presenting pathogen-associated molecular patterns (PAMPs) to the pattern recognition receptors (PRRs) of the innate immune system [2-5]. Yet, how specific repeats affect tumor evolution and shape the tumor immune microenvironment (TME) in a pro- or anti-tumorigenic manner remains poorly defined. Here, we integrate whole genome and total transcriptome data from a unique autopsy cohort of multiregional samples collected in pancreatic ductal adenocarcinoma (PDAC) patients, into a comprehensive evolutionary analysis. We find that more recently evolved S hort I nterspersed N uclear E lements (SINE), a family of retrotransposable repeats, are more likely to form immunostimulatory double-strand RNAs (dsRNAs). Consequently, younger SINEs are strongly co-regulated with RIG-I like receptor associated type-I interferon genes but anti-correlated with pro-tumorigenic macrophage infiltration. We discover that immunostimulatory SINE expression in tumors is regulated by either L ong I nterspersed N uclear E lements 1 (LINE1/L1) mobility or ADAR1 activity in a TP53 mutation dependent manner. Moreover, L1 retrotransposition activity tracks with tumor evolution and is associated with TP53 mutation status. Altogether, our results suggest pancreatic tumors actively evolve to modulate immunogenic SINE stress and induce pro-tumorigenic inflammation. Our integrative, evolutionary analysis therefore illustrates, for the first time, how dark matter genomic repeats enable tumors to co-evolve with the TME by actively regulating viral mimicry to their selective advantage.
AB - Overexpression of repetitive elements is an emerging hallmark of human cancers [1]. Diverse repeats can mimic viruses by replicating within the cancer genome through retrotransposition, or presenting pathogen-associated molecular patterns (PAMPs) to the pattern recognition receptors (PRRs) of the innate immune system [2-5]. Yet, how specific repeats affect tumor evolution and shape the tumor immune microenvironment (TME) in a pro- or anti-tumorigenic manner remains poorly defined. Here, we integrate whole genome and total transcriptome data from a unique autopsy cohort of multiregional samples collected in pancreatic ductal adenocarcinoma (PDAC) patients, into a comprehensive evolutionary analysis. We find that more recently evolved S hort I nterspersed N uclear E lements (SINE), a family of retrotransposable repeats, are more likely to form immunostimulatory double-strand RNAs (dsRNAs). Consequently, younger SINEs are strongly co-regulated with RIG-I like receptor associated type-I interferon genes but anti-correlated with pro-tumorigenic macrophage infiltration. We discover that immunostimulatory SINE expression in tumors is regulated by either L ong I nterspersed N uclear E lements 1 (LINE1/L1) mobility or ADAR1 activity in a TP53 mutation dependent manner. Moreover, L1 retrotransposition activity tracks with tumor evolution and is associated with TP53 mutation status. Altogether, our results suggest pancreatic tumors actively evolve to modulate immunogenic SINE stress and induce pro-tumorigenic inflammation. Our integrative, evolutionary analysis therefore illustrates, for the first time, how dark matter genomic repeats enable tumors to co-evolve with the TME by actively regulating viral mimicry to their selective advantage.
U2 - 10.1101/2023.05.19.541456
DO - 10.1101/2023.05.19.541456
M3 - Preprint
C2 - 37292765
T3 - bioRxiv
BT - Cancer cells co-evolve with retrotransposons to mitigate viral mimicry
PB - BioRxiv
ER -