Biology subjects

Hoyos, D.

Publications and source records attributed to Hoyos, D..

2 recordsLinked to original sources

bioRxiv2023

Cancer cells co-evolve with retrotransposons to mitigate viral mimicry

Overexpression of repetitive elements is an emerging hallmark of human cancers1. 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 system2-5. 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 Short Interspersed Nuclear Elements (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 Long Interspersed Nuclear Elements 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.

cancer biology↗

bioRxiv2023

Mechanism-guided quantification of LINE-1 reveals p53 regulation of both retrotransposition and transcription

Somatic activity of LINE-1 (L1) mobile elements has been implicated in cancer etiology, which may be related to the loss of p53-mediated regulation as a result of TP53 mutations. Quantifying the mechanisms of L1 regulation in cancer has been challenging. Here, we build a statistical model of L1 regulation by simultaneously quantifying L1 retrotransposition, L1 expression, and the fitness costs of mutated TP53 with precision. We first developed Total ReCall, an algorithm specifically tailored to the mechanisms of L1 reintegration, to detect L1 insertions from short-read whole-genome sequencing. Applying Total ReCall to high-quality data consisting of >750 paired tumor and normal samples from The Cancer Genome Atlas (TCGA) shows high L1 insertion heterogeneity among tumor types, with increased retrotransposition burden in lung squamous cell carcinoma, head and neck, and colon cancers. We next assessed the active RNA expression of intact L1 in >9,000 TCGA tumor samples, establishing, for the first time, a clear correlation between L1 expression and retrotransposition. Finally, we integrated the number of L1 insertions, L1 expression and a mathematical model of TP53 fitness into a multi-modal model of p53- mediated mechanisms of L1 regulation. We show that TP53 mutations enable retrotransposition both by disinhibiting L1 expression and enabling its reintegration and quantify the relative weights of this dual regulatory role. We demonstrate how mechanism-based multi-modal modeling applied at scale can statistically disentangle the complex interplay between canonical driver events in tumor evolution and retrotransposon activity.

cancer biology↗