Biology subjects

Marhon, S. A.

Publications and source records attributed to Marhon, S. A..

5 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

Retroelement decay by the exonuclease XRN1 is a viral mimicry dependency in cancer

Viral mimicry describes the immune response induced by endogenous stimuli such as dsRNA formed by endogenous retroelements. Activation of viral mimicry has the potential to kill cancer cells or augment anti-tumor immune response. Paradoxically, cancer cells frequently present a dysregulated epigenome, leading to increased expression of retroelements. We previously found that ADAR1 p150 upregulation is an adaptation mechanism to tolerate high retroelement-derived dsRNA levels, leading to a druggable dependency. Here, we systematically identified novel mechanisms of viral mimicry adaptation associated with cancer cell dependencies. We correlated the gene knockout sensitivity from the DepMap dataset and interferon stimulated gene (ISG) expression in the Cancer Cell Line Encyclopedia (CCLE) dataset of 1005 human cell lines and identified pathways such as RNA modification and nucleic acid metabolism. Among the top hits was the RNA decay protein XRN1 as an essential gene for the survival of a subset of cancer cell lines. XRN1-sensitive cancer cell lines have a high level of cytosolic dsRNA and high ISG expression. Furthermore, sensitivity to XRN1 knockout was mediated by MAVS and PKR activation, indicating that the cells die due to XRN1-dependent induction of viral mimicry. XRN1-resistant cell lines had low basal dsRNA levels, but became synthetically dependent on XRN1 upon treatment with viral mimicry inducing drugs such as 5-AZA-CdR or palbociclib. Finally, XRN1-dependency is partly independent of ADAR1 activity. These results confirm the potential for our ISG correlation analysis to discover novel regulators of viral mimicry and show that XRN1 activation is an adaptive mechanism to control high dsRNA stress induced by dysregulated retroelements in cancer cells and creates a dependency that can be explored for novel cancer therapies.

cell biology↗

bioRxiv2021

Repeats Mimic Immunostimulatory Viral Features Across a Vast Evolutionary Landscape

An emerging hallmark across human diseases - such as cancer, autoimmune and neurodegenerative disorders - is the aberrant transcription of typically silenced repetitive elements. Once active, a subset of repeats may be capable of "viral mimicry": the display of pathogen-associated molecular patterns (PAMPs) that can, in principle, bind pattern recognition receptors (PRRs) of the innate immune system and trigger inflammation. Yet how to quantify the landscape of viral mimicry and how it is shaped by natural selection remains a critical gap in our understanding of both genome evolution and the immunological basis of disease. We propose a theoretical framework to quantify selective forces on virus-like features as the entropic cost a sequence pays to hold a non-self PAMP and show our approach can predict classes of viral-mimicry within the human genome and across eukaryotes. We quantify the breadth and conservation of viral mimicry across multiple species for the first time and integrate selective forces into predictive evolutionary models. We show HSATII and intact LINE-1 (L1) are under selection to maintain CpG motifs, and specific Alu families likewise maintain the proximal presence of inverted copies to form double-stranded RNA (dsRNA). We validate our approach by predicting high CpG L1 ligands of L1 proteins and the innate receptor ZCCHC3, and dsRNA present both intracellularly and as MDA5 ligands. We conclude viral mimicry is a general evolutionary mechanism whereby genomes co-opt pathogen-associated features generated by prone repetitive sequences, likely offering an advantage as a quality control system against transcriptional dysregulation.

systems biology↗

bioRxiv2021

Identification of the Global miR-130a Targetome Reveals a Novel Role for TBL1XR1 in Hematopoietic Stem Cell Self-Renewal and t(8;21) AML

Gene expression profiling and proteome analysis of normal and malignant hematopoietic stem cells (HSC) point to shared core stemness properties. However, discordance between mRNA and protein signatures underscores an important role for post-transcriptional regulation by miRNAs in governing this critical nexus. Here, we identified miR-130a as a regulator of HSC self-renewal and differentiation. Enforced expression of miR-130a impaired B lymphoid differentiation and expanded long-term HSC. Integration of protein mass spectrometry and chimeric AGO2 eCLIP-seq identified TBL1XR1 as a primary miR-130a target, whose loss of function phenocopied miR-130a overexpression. Moreover, we found that miR-130a is highly expressed in t(8;21) AML where it is critical for maintaining the oncogenic molecular program mediated by AML1-ETO. Our study establishes that identification of the comprehensive miRNA targetome within primary cells enables discovery of novel genes and molecular networks underpinning stemness properties of normal and leukemic cells. HIGHLIGHTSO_LImiR-130a is a regulator of HSC self-renewal and lineage commitment C_LIO_LITBL1XR1 is a principal target of miR-130a C_LIO_LITBL1XR1 loss of function in HSPC phenocopies enforced expression of miR-130a C_LIO_LIElevated miR-130a levels maintain the AML1-ETO repressive program in t(8;21) AML C_LI

cell biology↗

bioRxiv2020

Mapping the Cellular Origin and Early Evolution of Leukemia in Down Syndrome

Children with Down syndrome have a 150-fold increased risk of developing myeloid leukemia, but the mechanism of predisposition is unclear. As Down syndrome leukemogenesis initiates during fetal development, we characterized the cellular context of preleukemic initiation and leukemic progression using gene editing in human disomic and trisomic fetal liver hematopoietic cells and xenotransplantation. GATA1 mutations caused transient preleukemia only when introduced into trisomy 21 long-term hematopoietic stem cells, where a subset of chromosome 21 miRNAs triggers predisposition to preleukemia. By contrast, progression to leukemia was independent of trisomy 21 and originated in various stem and progenitor cells through additional mutations in cohesin genes. CD117+/KIT cells mediated the propagation of preleukemia and leukemia, and functional KIT inhibition targeted preleukemic stem cells, blocking progression to leukemia.

cancer biology↗