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Ludwig Cancer Research had a stall at the Aylesbury relay for life event in Aylesbury Rugby Club on Saturday 5th July 2014.
Ratio of stemness to interferon signalling as a biomarker and therapeutic target of myeloproliferative neoplasm progression to acute myeloid leukaemia
SummaryProgression to aggressive secondary acute myeloid leukaemia (sAML) poses a significant challenge in the management of myeloproliferative neoplasms (MPNs). Since the physiopathology of MPN is closely linked to the activation of interferon (IFN) signalling and that AML initiation and aggressiveness is driven by leukaemia stem cells (LSCs), we investigated these pathways in MPN to sAML progression. We found that high IFN signalling correlated with low LSC signalling in MPN and AML samples, while MPN progression and AML transformation were characterized by decreased IFN signalling and increased LSC signature. A high LSC to IFN expression ratio in MPN patients was associated with adverse clinical prognosis and higher colony forming potential. Moreover, treatment with hypomethylating agents (HMAs) activates the IFN signalling pathway in MPN cells by inducing a viral mimicry response. This response is characterized by double‐stranded RNA (dsRNA) formation and MDA5/RIG‐I activation. The HMA‐induced IFN response leads to a reduction in LSC signature, resulting in decreased stemness. These findings reveal the frequent evasion of viral mimicry during MPN‐to‐sAML progression, establish the LSC‐to‐IFN expression ratio as a progression biomarker, and suggests that HMAs treatment can lead to haematological response in murine models by re‐activating dsRNA‐associated IFN signalling.
Chronic Viral Mimicry Induction following p53 Loss Promotes Immune Evasion.
SignificanceOur landmark discovery of viral mimicry characterized repetitive elements as immunogenic stimuli that cull cancer cells. If expressed repetitive elements cull cancer cells, why does every human cancer express repetitive elements? Our report offers an exciting advancement toward understanding this paradox and how to exploit this mechanism for cancer interception. See related commentary by Murayama and Cañadas, p. 670.
macroH2A2 antagonizes epigenetic programs of stemness in glioblastoma.
Self-renewal is a crucial property of glioblastoma cells that is enabled by the choreographed functions of chromatin regulators and transcription factors. Identifying targetable epigenetic mechanisms of self-renewal could therefore represent an important step toward developing effective treatments for this universally lethal cancer. Here we uncover an epigenetic axis of self-renewal mediated by the histone variant macroH2A2. With omics and functional assays deploying patient-derived in vitro and in vivo models, we show that macroH2A2 shapes chromatin accessibility at enhancer elements to antagonize transcriptional programs of self-renewal. macroH2A2 also sensitizes cells to small molecule-mediated cell death via activation of a viral mimicry response. Consistent with these results, our analyses of clinical cohorts indicate that high transcriptional levels of this histone variant are associated with better prognosis of high-grade glioma patients. Our results reveal a targetable epigenetic mechanism of self-renewal controlled by macroH2A2 and suggest additional treatment approaches for glioblastoma patients.
ADAR1: from basic mechanisms to inhibitors.
Adenosine deaminase acting on RNA 1 (ADAR1) converts adenosine to inosine in double-stranded RNA (dsRNA) molecules, a process known as A-to-I editing. ADAR1 deficiency in humans and mice results in profound inflammatory diseases characterised by the spontaneous induction of innate immunity. In cells lacking ADAR1, unedited RNAs activate RNA sensors. These include melanoma differentiation-associated gene 5 (MDA5) that induces the expression of cytokines, particularly type I interferons (IFNs), protein kinase R (PKR), oligoadenylate synthase (OAS), and Z-DNA/RNA binding protein 1 (ZBP1). Immunogenic RNAs 'defused' by ADAR1 may include transcripts from repetitive elements and other long duplex RNAs. Here, we review these recent fundamental discoveries and discuss implications for human diseases. Some tumours depend on ADAR1 to escape immune surveillance, opening the possibility of unleashing anticancer therapies with ADAR1 inhibitors.
PRMT inhibition induces a viral mimicry response in triple-negative breast cancer.
Triple-negative breast cancer (TNBC) is the most aggressive breast cancer subtype with the worst prognosis and few effective therapies. Here we identified MS023, an inhibitor of type I protein arginine methyltransferases (PRMTs), which has antitumor growth activity in TNBC. Pathway analysis of TNBC cell lines indicates that the activation of interferon responses before and after MS023 treatment is a functional biomarker and determinant of response, and these observations extend to a panel of human-derived organoids. Inhibition of type I PRMT triggers an interferon response through the antiviral defense pathway with the induction of double-stranded RNA, which is derived, at least in part, from inverted repeat Alu elements. Together, our results represent a shift in understanding the antitumor mechanism of type I PRMT inhibitors and provide a rationale and biomarker approach for the clinical development of type I PRMT inhibitors.
In vivo CRISPR screens identify a dual function of MEN1 in regulating tumor-microenvironment interactions.
Functional genomic screens in two-dimensional cell culture models are limited in identifying therapeutic targets that influence the tumor microenvironment. By comparing targeted CRISPR-Cas9 screens in a two-dimensional culture with xenografts derived from the same cell line, we identified MEN1 as the top hit that confers differential dropout effects in vitro and in vivo. MEN1 knockout in multiple solid cancer types does not impact cell proliferation in vitro but significantly promotes or inhibits tumor growth in immunodeficient or immunocompetent mice, respectively. Mechanistically, MEN1 knockout redistributes MLL1 chromatin occupancy, increasing H3K4me3 at repetitive genomic regions, activating double-stranded RNA expression and increasing neutrophil and CD8+ T cell infiltration in immunodeficient and immunocompetent mice, respectively. Pharmacological inhibition of the menin-MLL interaction reduces tumor growth in a CD8+ T cell-dependent manner. These findings reveal tumor microenvironment-dependent oncogenic and tumor-suppressive functions of MEN1 and provide a rationale for targeting MEN1 in solid cancers.
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 double-stranded RNA (dsRNA) from endogenous retroelements. Activation of viral mimicry has the potential to kill cancer cells or augment anti-tumor immune responses. Here, we systematically identify mechanisms of viral mimicry adaptation associated with cancer cell dependencies. Among the top hits is the RNA decay protein XRN1 as an essential gene for the survival of a subset of cancer cell lines. XRN1 dependency is mediated by mitochondrial antiviral signaling protein and protein kinase R activation and is associated with higher levels of cytosolic dsRNA, higher levels of a subset of Alus capable of forming dsRNA, and higher interferon-stimulated gene expression, indicating that cells die due to induction of viral mimicry. Furthermore, dsRNA-inducing drugs such as 5-aza-2'-deoxycytidine and palbociclib can generate a synthetic dependency on XRN1 in cells initially resistant to XRN1 knockout. These results indicate that XRN1 is a promising target for future cancer therapeutics.
Repeats mimic pathogen-associated patterns across a vast evolutionary landscape.
An emerging hallmark of many human diseases is transcription of typically silenced repetitive DNA containing pathogen-associated molecular patterns (PAMPs). These PAMPs engage the innate immune system via pattern recognition receptors (PRRs)-a phenomenon known as viral mimicry. We propose a statistical physics framework to quantify viral mimicry by measuring "selective forces" that enrich PAMPs compared to a genome-wide reference distribution. We validate our predictions by identifying repeats that bind different PRRs and show potential viral mimics in different repeat families across eukaryotic genomes, suggesting shared mechanisms drive emergence and retention. We propose two non-exclusive evolutionary hypotheses. The first "repeat-centric" hypothesis posits PAMPs are integral to the repeat life cycle and are therefore enriched as they mediate repeat expansion. The second "organism-centric" hypothesis proposes viral mimicry functions as a cell-intrinsic feedback mechanism for sensing and reacting to transcriptional dysregulation, which provides a selective pressure to maintain PAMPs in genomes.
Inhibiting EZH2 targets atypical teratoid rhabdoid tumor by triggering viral mimicry via both RNA and DNA sensing pathways.
Inactivating mutations in SMARCB1 confer an oncogenic dependency on EZH2 in atypical teratoid rhabdoid tumors (ATRTs), but the underlying mechanism has not been fully elucidated. We found that the sensitivity of ATRTs to EZH2 inhibition (EZH2i) is associated with the viral mimicry response. Unlike other epigenetic therapies targeting transcriptional repressors, EZH2i-induced viral mimicry is not triggered by cryptic transcription of endogenous retroelements, but rather mediated by increased expression of genes enriched for intronic inverted-repeat Alu (IR-Alu) elements. Interestingly, interferon-stimulated genes (ISGs) are highly enriched for dsRNA-forming intronic IR-Alu elements, suggesting a feedforward loop whereby these activated ISGs may reinforce dsRNA formation and viral mimicry. EZH2i also upregulates the expression of full-length LINE-1s, leading to genomic instability and cGAS/STING signaling in a process dependent on reverse transcriptase activity. Co-depletion of dsRNA sensing and cytoplasmic DNA sensing completely rescues the viral mimicry response to EZH2i in SMARCB1-deficient tumors.
Mechanical confinement governs phenotypic plasticity in melanoma.
Phenotype switching is a form of cellular plasticity in which cancer cells reversibly move between two opposite extremes: proliferative versus invasive states1,2. Although it has long been hypothesized that such switching is triggered by external cues, the identity of these cues remains unclear. Here we demonstrate that mechanical confinement mediates phenotype switching through chromatin remodelling. Using a zebrafish model of melanoma coupled with human samples, we profiled tumour cells at the interface between the tumour and surrounding microenvironment. Morphological analysis of interface cells showed elliptical nuclei, suggestive of mechanical confinement by the adjacent tissue. Spatial and single-cell transcriptomics demonstrated that interface cells adopted a gene program of neuronal invasion, including the acquisition of an acetylated tubulin cage that protects the nucleus during migration. We identified the DNA-bending protein HMGB2 as a confinement-induced mediator of the neuronal state. HMGB2 is upregulated in confined cells, and quantitative modelling revealed that confinement prolongs the contact time between HMGB2 and chromatin, leading to changes in chromatin configuration that favour the neuronal phenotype. Genetic disruption of HMGB2 showed that it regulates the trade-off between proliferative and invasive states, in which confined HMGB2high tumour cells are less proliferative but more drug-resistant. Our results implicate the mechanical microenvironment as a mechanism that drives phenotype switching in melanoma.
IFNγ-induced PD-L1+MHC II+ macrophages and Tim-3+ tumor-reactive CD8+ T cells predict a response to anti-PD-1 therapy in tumor-bearing mice.
While immune checkpoint inhibitors have led to durable responses in various cancer types, a substantial proportion of patients do not respond to these interventions. To uncover potential factors associated with a positive response to immunotherapy, we used a bilateral tumor model using P815 mastocytoma implanted in DBA/2 mice. In this model, only a fraction of tumor-bearing mice responds to anti-PD-1 treatment. Thus, it provides a valuable model to explore the influence of the tumor microenvironment (TME) in determining the efficacy of immune checkpoint blockade (ICB)-based immunotherapies. It also allows for the analysis of a pretreatment tumor and inference of its treatment outcome based on the response observed in the contralateral tumor. Herein, we report that tumor-reactive CD8+ T-cell clones expressing high levels of Tim-3 were associated with a positive antitumor response following anti-PD-1 administration. Our study also revealed distinct differentiation dynamics in tumor-infiltrating myeloid cells in responding and non-responding mice. An IFNγ-enriched TME promoted the differentiation of monocytes into PD-L1posMHC IIhigh cells in mice responding to immunotherapy. Monocytes present in the TME of non-responding mice failed to reach the same final stage of differentiation trajectory, suggesting that an altered monocyte to macrophage differentiation route may hamper the response to ICB. These insights will direct future research towards a temporal analysis of tumor-associated macrophages (TAMs), aiming to identify factors responsible for transitions between differentiation states within the TME. This approach may pave the way to novel strategies to enhance the efficacy of PD-1 blockade.
Nitric oxide promotes cysteine N-degron proteolysis through control of oxygen availability
Selected proteins containing an N-terminal cysteine (Nt-Cys) are subjected to rapid, O 2 -dependent proteolysis via the Cys/Arg-branch of the N-degron pathway. Cysteine dioxygenation is catalyzed in mammalian cells by 2-aminoethanethiol dioxygenase (ADO), an enzyme that manifests extreme O 2 sensitivity. The canonical substrates of this pathway in mammalia are the regulators of G-protein signaling 4, 5, and 16, as well as interleukin-32. In addition to operating as an O 2 -sensing mechanism, this pathway has previously been described as a sensor of nitric oxide (NO), with robust effects on substrate stability upon modulation of NO bioavailability being widely demonstrated. Despite this, no mechanism to describe the action of NO on the Cys/Arg N-degron pathway has yet been substantiated. We demonstrate that NO can regulate the stability of Cys N-degron substrates indirectly via the regulation of ADO cosubstrate availability. Through competitive, O 2 -dependent inhibition of cytochrome C oxidase, NO can substantially modify cellular O 2 consumption rate and, in doing so, alter the availability of O 2 for Nt-Cys dioxygenation. We show that this increase in O 2 availability in response to NO exposure is sufficient to alter both dynamic and steady-state ADO substrate levels. It is likely that this mechanism operates to couple O 2 supply and mitochondrial respiration with responses to G-protein-coupled receptor stimulation.
Platelets sequester extracellular DNA, capturing tumor-derived and free fetal DNA.
Platelets are anucleate blood cells vital for hemostasis and immunity. During cell death and aberrant mitosis, nucleated cells release DNA, resulting in "cell-free" DNA in plasma (cfDNA). An excess of cfDNA is deleterious. Given their ability to internalize pathogen-derived nucleic acids, we hypothesized that platelets may also clear endogenous cfDNA. We found that, despite lacking a nucleus, platelets contained a repertoire of DNA fragments mapping across the nuclear genome. We detected fetal DNA in maternal platelets and cancer-derived DNA in platelets from patients with premalignant and cancerous lesions. As current liquid biopsy approaches utilize platelet-depleted plasma, important genetic information contained within platelets is being missed. This study establishes a physiological role for platelets that has not previously been highlighted, with broad translational relevance.
The Ebola Data Platform: A prospective, standardised, clinical dataset collected during the 2013-2016 West African Ebola outbreak.
The Ebola Data Platform (EDP) was developed to strengthen knowledge and capacity across health, research, and humanitarian communities to reduce the impact of Ebola through responsible data use. This collaborative initiative was established by West African governments, NGOs, academic organisations, and intra-governmental health organisations directly involved in the 2013-2016 West African Ebola outbreak. The platform was established to provide a centralised, standardised dataset of individual patient data collected during the outbreak for the purpose of research to improve Ebola treatment and control, and includes over 13,600 patient records of individuals infected and treated from 22 different Ebola treatment centres across Guinea, Sierra Leone, Liberia, and Nigeria. Patient data are available from treatment centre triage and admission, inpatient clinical observations, and outcomes, with outpatient follow-up available for some datasets. Data include signs and symptoms, pre-existing comorbidities, vital signs, laboratory testing, treatments, complications, dates of admission and discharge, mortality, viral strains, and other data. This publication describes characteristics of the EDP dataset, its architecture, methods for data access and tools for utilising the dataset.