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Nguyen, L.

Publications and source records attributed to Nguyen, L..

At least 55 records · Page 3Linked to original sources

Autophagy disruption and mitochondrial stress precede photoreceptor necroptosis in multiple mouse models of inherited retinal disorders.

Inherited retinal diseases (IRDs) are a leading cause of blindness worldwide. One of the greatest barriers to developing treatments for IRDs is the heterogeneity of these disorders, with causative mutations identified in over 280 genes. It is therefore a priority to find therapies applicable to a broad range of genetic causes. To do so requires a greater understanding of the common or overlapping molecular pathways that lead to photoreceptor death in IRDs and the molecular processes through which they converge. Here, we characterise the contribution of different cell death mechanisms to photoreceptor degeneration and loss throughout disease progression in humanised mouse models of IRDs. Using single-cell transcriptomics, we identify common transcriptional signatures in degenerating photoreceptors. Further, we show that in genetically and functionally distinct IRD models, common early defects in autophagy and mitochondrial damage exist, triggering photoreceptor cell death by necroptosis in later disease stages. These results suggest that, regardless of the underlying genetic cause, these pathways likely contribute to cell death in IRDs. These insights provide potential therapeutic targets for novel, gene-agnostic treatments for IRDs applicable to the majority of patients.

cell biology↗

DNA Origami Signal Amplification in LateralFlow Immunoassays

Lateral flow immunoassays (LFIAs) enable a rapid detection of analytes in a simple, paper-based test format. Despite their multiple advantages, such as low cost and ease of use, their low sensitivity compared to laboratory-based testing limits their use in e.g. many critical point-of-care applications. Here, we present a DNA origami-based signal amplification technology for LFIAs. DNA origami is used as a structurally precise adapter to connect detection antibodies to tailored numbers of signal-generating labels. As a proof of concept, we apply the DNA origami signal amplification in a sandwich-based LFIA for the detection of cardiac troponin I (cTnI) in human serum. We show a 55-fold improvement of the assay sensitivity with 40 nm gold nanoparticle labels and an adjustable signal amplification of up to 125-fold with fluorescent dyes. The technology is compatible with a wide range of existing analytes, labels, and sample matrices, and presents a modular approach for improving the sensitivity and reliability of lateral flow testing.

biophysics↗

Nanofibrous Wound Dressing with a Smart Drug Delivery System: Poly(N-Isopropylacrylamide)-Conjugated Polycaprolactone Nanofibers Loaded with Curcumin

In response to clinical demands for advanced wound dressings, a "smart bandage" was developed by combining polycaprolactone (PCL) nanofibers and the thermoresponsive polymer poly(N-isopropylacrylamide) (PNIPAAm). This bandage incorporates curcumin, an anti-inflammatory and antioxidant agent, to enhance wound healing. The LCST of PNIPAAm (32{degrees}C) enables an "on-off" drug delivery system, transitioning from a hydrophilic coil to a hydrophobic state. The nanofiber matrix was characterized using FTIR spectroscopy, SEM, water contact angle, and dynamic mechanical analysis. Curcumin release was assessed both above and below the LCST. The bandage is comfortable, easy to apply and remove, and promotes rapid wound healing. In vitro studies confirmed its non-toxicity to human dermal fibroblast cells. This "smart bandage" represents a significant advancement in wound care, with the potential to meet clinical requirements and enhance patient compliance, offering controlled drug delivery combined with the therapeutic benefits of curcumin.

bioengineering↗

Tuning single-molecule ClyA nanopore tweezers for real-time tracking ofthe conformational dynamics of West Nile viral NS2B/NS3 protease

The flaviviral NS2B/NS3 protease is a conserved enzyme required for flavivirus replication. Its highly dynamic conformation poses major challenges but also offers opportunities for antiviral inhibition. Here, we established a nanopore tweezers-based platform to monitor NS2B/NS3 conformational dynamics in real-time. Molecular simulations coupled with electrophysiology revealed that the protease could be captured in the middle of the ClyA nanopore lumen, stabilized mainly by dynamic electrostatic interactions. We designed a new Salmonella typhi ClyA nanopore with enhanced nanopore/protease interaction that can resolve the open and closed states at the single-molecule level for the first time. We demonstrated that the tailored ClyA could track the conformational transitions of the West Nile NS2B/NS3 protease and unravel the conformational energy landscape of various protease constructs through population and kinetic analysis. The new ClyA-protease platform paves a way to high-throughput screening strategies for discovering new allosteric inhibitors that target the NS2B and NS3 interface.

biophysics↗

SARS-CoV2 infection triggers reactive astrocyte states and inflammatory conditions in long-term Human Cortical Organoids

SARS-CoV2, severe acute respiratory syndrome coronavirus 2, is frequently associated with neurological manifestations. Despite the presence of mild to severe CNS-related symptoms in a cohort of patients, there is no consensus whether the virus can infect directly brain tissue or if the symptoms in patients are a consequence of peripheral infectivity of the virus. Here, we use long-term human stem cell-derived cortical organoids to assess SARS-CoV2 infectivity of brain cells and unravel the cell-type tropism and its downstream pathological effects. Our results show consistent and reproducible low levels of SARS-CoV2 infection of astrocytes, deep projection neurons, upper callosal neurons and inhibitory neurons in 6 months human cortical organoids. Interestingly, astrocytes showed the highest infection rate among all infected cell populations that led to increased presence of reactive states. Further, transcriptomic analysis revealed overall changes in expression of genes related to cell metabolism, astrocyte activation and, inflammation and further, upregulation of cell survival pathways. Thus, local and minor infectivity of SARS-CoV2 in the brain may induce widespread adverse effects and may lead to resilience of dysregulated neurons and astrocytes within an inflammatory environment.

neuroscience↗

GotGlycans: Role of N343 Glycosylation on the SARS-CoV-2 S RBD Structure and Co-Receptor Binding Across Variants of Concern

Glycosylation of the SARS-CoV-2 spike (S) protein represents a key target for viral evolution because it affects both viral evasion and fitness. Successful variations in the glycan shield are difficult to achieve though, as protein glycosylation is also critical to folding and to structural stability. Within this framework, the identification of glycosylation sites that are structurally dispensable can provide insight into the evolutionary mechanisms of the shield and inform immune surveillance. In this work we show through over 45 s of cumulative sampling from conventional and enhanced molecular dynamics (MD) simulations, how the structure of the immunodominant S receptor binding domain (RBD) is regulated by N-glycosylation at N343 and how this glycans structural role changes from WHu-1, alpha (B.1.1.7), and beta (B.1.351), to the delta (B.1.617.2) and omicron (BA.1 and BA.2.86) variants. More specifically, we find that the amphipathic nature of the N-glycan is instrumental to preserve the structural integrity of the RBD hydrophobic core and that loss of glycosylation at N343 triggers a specific and consistent conformational change. We show how this change allosterically regulates the conformation of the receptor binding motif (RBM) in the WHu-1, alpha and beta RBDs, but not in the delta and omicron variants, due to mutations that reinforce the RBD architecture. In support of these findings, we show that the binding of the RBD to monosialylated ganglioside co-receptors is highly dependent on N343 glycosylation in the WHu-1, but not in the delta RBD, and that affinity changes significantly across VoCs. Ultimately, the molecular and functional insight we provide in this work reinforces our understanding of the role of glycosylation in protein structure and function and it also allows us to identify the structural constraints within which the glycosylation site at N343 can become a hotspot for mutations in the SARS-CoV-2 S glycan shield.

biophysics↗

Engineering the microstructure and spatial bioactivity of MAP scaffolds in vitro instructs neovascularization in vivo

In tissues where the vasculature is either lacking or abnormal, biomaterials can be designed to promote vessel formation and enhance tissue repair. In this work, we independently tune the microstructure and bioactivity of microporous annealed particle (MAP) scaffolds to guide cell patterning in 3D and promote de novo assembly of endothelial progenitor-like cells into vessels. We implement both in silico characterization and in vitro experimentation to elucidate an optimal scaffold formulation for vessel formation. We determine that MAP scaffolds with pore volumes on the same order of magnitude as cells facilitate cell growth and vacuole formation. We achieve spatial control over cell spreading by incorporating adhesive microgels in well-mixed, heterogeneous MAP scaffolds. While we demonstrate that integrin engagement is the primary driver of network formation in these materials, introducing adhesive microgels loaded with heparin nanoparticles leads to the formation of vascular tubes after 3 days in culture. We then show in vivo that this unique scaffold formulation enhances vessel maturation in a wound healing model and instructs differential vascular patterning in the tumor microenvironment. Taken together, this work determines the optimal microstructure and ligand presentation within MAP scaffolds that lead to vascular constructs in vitro and facilitate neovascularization in vivo.

bioengineering↗

Overlap and divergence of neural circuits mediating distinct behavioral responses to sugar

A single sensory cue can elicit diverse behavioral responses. For example, the taste of sugar robustly promotes feeding1, 2 but also influences other behaviors, such as altering locomotor patterns to maximize food-finding3, 4 or conferring a rewarding value onto associated contexts or cues.5-7 Here, we investigate how sweet taste elicits multiple appetitive behaviors in Drosophila. Are different sugar-evoked behaviors coordinately regulated? At what point does the sugar circuit diverge into different pathways that drive distinct behaviors? We first established an optogenetic paradigm to study the effects of sugar taste on locomotion, spatial preference, and associative learning. We then tested how different sugar-evoked behaviors were modulated by internal and external factors, including hunger, diet, or the presence of an aversive taste. Different behaviors were generally modulated in similar ways, but we also observed some differences that reveal selective modulation of specific behavioral pathways. Finally, we investigated where the sugar taste circuit diverges into different behavioral pathways. A recent study identified a sensory-motor circuit comprising five layers of neurons that drives the initiation of feeding in response to sugar.8 By individually manipulating each of these neurons, we show that circuits mediating different innate responses to sugar are partially overlapping and begin to diverge at the level of second- and third-order neurons, whereas circuits for innate versus learned behaviors may diverge at the first synapse. Connectomic analyses reveal distinct subcircuits that mediate different behaviors. Together, these studies provide insight into how neural circuits are organized to elicit diverse behavioral responses to a single stimulus.

neuroscience↗

Regulation of interferon signaling by transposon exonization

SummaryInnate immune signaling is essential for clearing pathogens and damaged cells, and must be tightly regulated to avoid excessive inflammation or autoimmunity. Here, we found that the alternative splicing of exons derived from transposable elements is a key mechanism controlling immune signaling in human cells. By analyzing long-read transcriptome datasets, we identified numerous transposon exonization events predicted to generate functional protein variants of immune genes, including the type I interferon receptor IFNAR2. We demonstrated that the transposon-derived isoform of IFNAR2 is more highly expressed than the canonical isoform in almost all tissues, and functions as a decoy receptor that potently inhibits interferon signaling including in cells infected with SARS-CoV-2. Our findings uncover a primate-specific axis controlling interferon signaling and show how a transposon exonization event can be co-opted for immune regulation.

genomics↗

Genetic modifiers of APOBEC-induced mutagenesis

The cytidine deaminases APOBEC3A and APOBEC3B (A3B) are prominent mutators of human cancer genomes. However, tumor-specific genetic modulators of APOBEC-induced mutagenesis are poorly defined. Here, we utilized a screen to identify 61 gene deletions that increase A3B-induced mutations in yeast. Also, we determined whether each deletion was epistatic with UNG1 loss, which indicated whether the encoded factors participate in the error-free bypass of A3B/Ung1-dependent abasic sites or suppress A3B-catalyzed deamination by protecting against aberrant formation of single stranded DNA (ssDNA). Additionally, we determined that the mutation spectra of A3B-induced mutations revealed genotype-specific patterns of strand-specific ssDNA formation and nucleotide incorporation across APOBEC-induced lesions. Combining these three metrics we were able to establish a multifactorial signature of APOBEC-induced mutations specific to (1) failure to remove H3K56 acetylation, which results in extremely high A3B-induced mutagenesis, (2) defective CTF18-RFC complex function, which results in high levels of A3B induced mutations specifically on the leading strand template that synergistically increase with loss of UNG1, and (3) defective HR-mediated bypass of APOBEC-induced lesions, which were epistatic with Ung1 loss and result from increased Rev1-mediated C-to-G substitutions. We extended these results by analyzing mutation data for human tumors and found BRCA1/2-deficient breast cancer tumors display 3- to 4-fold more APOBEC-induced mutations. Mirroring our results in yeast, for BRCA1/2 deficient tumors Rev1-mediated C-to-G substitutions are solely responsible for increased APOBEC-signature mutations and these mutations occur on the lagging strand during DNA replication. Together these results identify important factors that influence the dynamics of DNA replication and likely the abundance of APOBEC-induced mutation during tumor progression as well as a novel mechanistic role for BRCA1/2 during HR-dependent lesion bypass of APOBEC-induced lesions during cancer cell replication.

genomics↗

Structure-function analysis of a calcium-independent metacaspase reveals a novel proteolytic pathway for lateral root emergence

Metacaspases are part of an evolutionarily broad family of multifunctional cysteine proteases, involved in disease and normal development. Despite the extensive study of metacaspases in the two decades since their discovery, the structure-function relationship of metacaspases remains poorly understood. Furthermore, previous studies on their function have been thwarted by the redundancy in gene copy number and potential phenotypic suppression of genetic mutations, especially in plants. Here, we have solved the X-ray crystal structure of an Arabidopsis thaliana type II metacaspase (AtMCA-IIf) that belongs to a particular sub-group that does not require calcium ions for activation. Compared to crystal structures of other metacaspases and caspases, the AtMCA-IIf active site is structurally similar and poses a conundrum for the catalytic mechanism of the cysteine-histidine dyad. To study metacaspase activity in plants, we developed an in vitro chemical screen to identify small molecule metacaspase inhibitors. Several hits with a minimal thioxodihydropyrimidine-dione (TDP) structure were identified, some being specific inhibitors of AtMCA-IIf. We provide a mechanistic basis for inhibition by the TDP-containing compounds through molecular docking onto the AtMCA-IIf crystal structure. Finally, a TDP-containing compound (TDP6) was effective at inhibiting lateral root emergence in vivo, likely through the inhibition of metacaspases that are specifically expressed in the endodermal cells overlaying developing lateral root primordia. In the future, the small compound inhibitors and crystal structure of AtMCA-IIf can be used to study metacaspases in various other species, such as important human pathogens including those causing neglected diseases.

plant biology↗

E4F1 COORDINATES PYRUVATE METABOLISM AND THE ACTIVITY OF THE ELONGATOR COMPLEX TO ENSURE PROTEIN TRANSLATION FIDELITY DURING NEURONAL DEVELOPMENT

Pyruvate metabolism defects lead to severe neuropathies such as the Leigh syndrome (LS) but the molecular mechanisms underlying neuronal cell death remain poorly understood. Here, we unravel a connection between pyruvate metabolism and the regulation of the epitranscriptome that is relevant to LS pathogenesis. We identified the transcription factor E4F1 as a key coordinator of AcetylCoenzyme A (AcCoA) production by the pyruvate dehydrogenase complex (PDC) and its utilization as an essential co-factor by the Elongator complex to acetylate tRNAs at the wobble position uridine 34 (U34). E4F1-mediated direct transcriptional regulation of Dlat and Elp3, two genes encoding key subunits of the PDC and of the Elongator complex, respectively, ensured proper translation fidelity and cell survival in the central nervous system (CNS) during mouse embryonic development. Furthermore, analysis of PDH-deficient cells highlighted a crosstalk linking the PDC to ELP3 expression that is perturbed in LS patients.

developmental biology↗

The SARS-CoV-2 spike N-terminal domain engages 9-O-acetylated α2-8-linked sialic acids

SARS-CoV-2 viruses engage ACE2 as a functional receptor with their spike protein. The S1 domain of the spike protein contains a C-terminal receptor-binding domain (RBD) and an N-terminal domain (NTD). The NTD of other coronaviruses includes a glycan-binding cleft. However, for the SARS-CoV-2 NTD protein-glycan binding was only observed weakly for sialic acids with highly sensitive methods. Amino acid changes in the NTD of Variants of Concern (VoC) shows antigenic pressure, which can be an indication of NTD-mediated receptor binding. Trimeric NTD proteins of SARS-CoV-2, Alpha, Beta, Delta, and Omicron did not reveal a receptor binding capability. Unexpectedly, the SARS-CoV-2 Beta subvariant strain (501Y.V2-1) NTD binding to Vero E6 cells was sensitive to sialidase pretreatment. Glycan microarray analyses identified a putative 9-O-acetylated sialic acid as a ligand, which was confirmed by catch-and-release ESI-MS, STD-NMR analyses, and a graphene-based electrochemical sensor. The Beta (501Y.V2-1) variant attained an enhanced glycan binding modality in the NTD with specificity towards 9-O-acetylated structures, suggesting a dual-receptor functionality of the SARS-CoV-2 S1 domain, which was quickly selected against. These results indicate that SARS-CoV-2 can probe additional evolutionary space, allowing binding to glycan receptors on the surface of target cells. Graphical abstract O_FIG O_LINKSMALLFIG WIDTH=76 HEIGHT=200 SRC="FIGDIR/small/507904v2_ufig1.gif" ALT="Figure 1"> View larger version (31K): org.highwire.dtl.DTLVardef@1f98a70org.highwire.dtl.DTLVardef@1efc119org.highwire.dtl.DTLVardef@16e8bc6org.highwire.dtl.DTLVardef@9a74e6_HPS_FORMAT_FIGEXP M_FIG C_FIG SynopsisCoronaviruses utilize their N-terminal domain (NTD) for initial reversible low-affinity interaction to (sialylated) glycans. This initial low-affinity/high-avidity engagement enables viral surfing on the target membrane, potentially followed by a stronger secondary receptor interaction. Several coronaviruses, such as HKU1 and OC43, possess a hemagglutinin-esterase for viral release after sialic acid interaction, thus allowing viral dissemination. Other coronaviruses, such as MERS-CoV, do not possess a hemagglutinin-esterase, but interact reversibly to sialic acids allowing for viral surfing and dissemination. The early 501Y.V2-1 subvariant of the Beta SARS-CoV-2 Variant of Concern has attained a receptor-binding functionality towards 9-O-acetylated sialic acid using its NTD. This binding functionality was selected against rapidly, most likely due to poor dissemination. Ablation of sialic acid binding in more recent SARS-CoV-2 Variants of Concern suggests a fine balance of sialic acid interaction of SARS-CoV-2 is required for infection and/or transmission.

molecular biology↗

JNK signalling regulates self-renewal of proliferative urine-derived renal progenitor cells via inhibition of ferroptosis

With a global increase in chronic kidney disease patients, alternatives to dialysis and organ transplantation are needed. Stem cell-based therapies could be one possibility to treat chronic kidney disease. Here, we used multipotent urine-derived renal progenitor cells (UdRPCs) to study nephrogenesis. UdRPCs treated with the JNK inhibitor-AEG3482, displayed decreased proliferation and downregulated transcription of cell cycle-associated genes as well as the kidney progenitor markers -SIX2, CITED1, and SALL1. In addition, levels of activated SMAD2/3, which is associated with the maintenance of self-renewal in UdRPCs, were decreased. JNK inhibition resulted in less efficient oxidative phosphorylation and more lipid peroxidation via ferroptosis-an iron-dependent non-apoptotic cell death pathway linked to various forms of kidney disease. Our study reveals the importance of JNK signalling in maintaining self-renewal as well as protection against ferroptosis in SIX2-positive UdRPCs. We propose that UdRPCs can be used for modelling ferroptosis-induced kidney diseases.

cell biology↗

A Closed-Form Adaptation of the Hodgkin-Huxley Membrane Potential and its Synthesis to a Novel Electric Circuit.

In a succession of journal papers published over 65 years ago, Sir Alan Lloyd Hodgkin and Sir Andrew Fielding Huxley discovered what now forms our contemporary understanding of excitation in nerve, and how axons conduct the action potential. Hodgkin and Huxley demonstrated that the nerve action potential is the result of a depolarizing event across a cell membrane. In an elegant theoretical framework, they established that when this depolarization event is complete, an abrupt increase in voltage gets produced that propagates longitudinally along the axon, accompanied by changes in axial conductance. Notwithstanding the elegance of Hodgkin and Huxleys incisive and explicative series of discoveries, their model is relatively complex, relies on no small number of stochastic factors, and has no analytical solution; solving for the membrane action potential and the ionic currents requires integrations approximated using numerical methods. In this paper, we present a closed-form adaptation of the Hodgkin-Huxley membrane voltage potential. The basis of our model is rooted in core conductor theory and the cable properties of neurons, with fitting parameters adapted to the classical Hodgkin-Huxley model of excitation in nerve. From this model we synthesize a novel analog circuit that simulates the dynamics of a single action potential bioelectrically equivalent to the classical Hodgkin-Huxley membrane potential. The primary novelty of our model is that it offers a bioconductive, thermodynamic, and electromagnetic explanation of how an action potential propagates in nerve in a single mathematical construct. This is in contrast to the traditional Hodgkin-Huxley equations of ionic hypothesis, which are not analytically compliant. Computational results of our model are supported by well-established quantitative descriptions of Hodgkin-Huxleys voltage response in the membrane of an axon. Our findings provide a mechanistic understanding of how intracellular conductance, the thermodynamics of magnetization, and current modulation function together to generate excitation in nerve in a unified closed-form description. In the same manner with Hodgkin-Huxleys findings, the model presented here corroborates (1) that the action potential is the result of a depolarizing event across a cell membrane; (2) that a complete depolarization event is followed by an abrupt increase in voltage that propagates longitudinally along the axon; (3) that the latter is accompanied by a considerable increase in membrane conductance. The work presented in this paper provides compelling evidence that three basic factors contribute to the propagated signaling in the membrane of an axon in a single, closed-form model. From our model, we synthesize a novel analog conductance-level circuit that simulates the dynamics of a single action potential bioelectrically equivalent to the classical Hodgkin-Huxley membrane potential. Its anticipated this work will compel those in biophysics, physical biology, and in the computational neurosciences to probe deeper into the classical and quantum features of membrane magnetization and signaling. Furthermore, its hoped that subsequent investigations of this sort will be advanced by the computational features of this model without having to resort to numerical methods of analysis. AttributionA portion of this work is reprinted from R.F. Melendy, Resolving the biophysics of axon transmembrane polarization in a single closed-form description [1]. Journal of Applied Physics, 118(24), Copyright (C) (2015); and from R.F. Melendy, A subsequent closed-form description of propagated signaling phenomena in the membrane of an axon [2]. AIP Advances, 6(5), Copyright (C) (2016), with the permission of AIP Publishing. Said published works are copyright protected by Robert. F. Melendy, Ph.D., and the AIP journals in which these articles appear. Under [§]107 of the Copyright Act of 1976, allowance is made for "fair use" for purposes such as criticism, comment, news reporting, teaching, scholarship, and research. Fair use is a use permitted by copyright statute that might otherwise be infringing. Nonprofit, educational (i.e., teaching, scholarship, and research) or personal use tips the balance in favor of fair use. SummaryThis work provides evidence that three basic factors contribute to propagated signaling in the membrane of an axon. The contributing factors are unified in a closed-form description. From this closed-form model we synthesize a novel analog circuit that simulates the dynamics of a single action potential that is bioelectrically equivalent to the classical Hodgkin-Huxley membrane potential.

biophysics↗

Mechanistic insights of glucosome condensate formation by stochastic modeling approaches

Human liver-type phosphofructokinase 1 (PFKL) has been shown to play a scaffolder role to recruit and organize glycolytic and gluconeogenic enzymes into a multienzyme metabolic condensate, the glucosome, that regulates glucose flux in living human cells. However, it has been challenging to characterize which factors control phase separation of PFKL and so glucosome condensates in a living cell, thus hampering to understand a mechanism of reversible glucosome formation and its functional contribution to human cells. In this work, we developed a stochastic model in silico using the principal of Langevin dynamics to investigate how biological properties of PFKL contribute to the formation of glucosome condensates. Molecular dynamics simulation using the Large-scale Atomic/Molecular Massively Parallel Simulator (LAMMPS) revealed the importance of an intermolecular interaction between PFKLs, an effective concentration of PFKL at a region of interest, and a pre-organization of its own self-assembly in formation of PFKL condensates and control of their sizes. Such biological properties that define intracellular dynamics of PFKL appear to be essential for phase separation of PFKL and thus formation of glucosome condensates. Collectively, our computational study provides mechanistic insights of glucosome formation, particularly an initiation step through the formation of PFKL condensates in living human cells.

biochemistry↗

Pan-cancer whole genome comparison of primary and metastatic solid tumors

Metastatic cancer remains almost inevitably a lethal disease. A better understanding of disease progression and response to therapies therefore remains of utmost importance. Here, we characterize the genomic differences between early-stage untreated primary tumors and late-stage treated metastatic tumors using a harmonized pan-cancer (re-)analysis of 7,152 whole-genome-sequenced tumors. In general, our analysis shows that metastatic tumors have a low intra-tumor heterogeneity, high genomic instability and increased frequency of structural variants with comparatively a modest increase in the number of small genetic variants. However, these differences are cancer type specific and are heavily impacted by the exposure to cancer therapies. Five cancer types, namely breast, prostate, thyroid, kidney clear carcinoma and pancreatic neuroendocrine, are a clear exception to the rule, displaying an extensive transformation of their genomic landscape in advanced stages. These changes were supported by increased genomic instability and involved substantial differences in tumor mutation burden, clock-based molecular signatures and the landscape of driver alterations as well as a pervasive increase in structural variant burden. The majority of cancer types had either moderate genomic differences (e.g., cervical and colorectal cancers) or highly consistent genomic portraits (e.g., ovarian cancer and skin melanoma) when comparing early- and late-stage disease. Exposure to treatment further scars the tumor genome and introduces an evolutionary bottleneck that selects for known therapy-resistant drivers in approximately half of treated patients. Our data showcases the potential of whole-genome analysis to understand tumor evolution and provides a valuable resource to further investigate the biological basis of cancer and resistance to cancer therapies.

genomics↗

TE invasion fuels molecular adaptation in laboratory populations of Drosophila melanogaster

Transposable elements are mobile genetic parasites that frequently invade new host genomes through horizontal transfer. Invading TEs often exhibit a burst of transposition, followed by reduced transposition rates as repression evolves in the host. We recreated the horizontal transfer of P-element DNA transposons into a D. melanogaster host, and followed the expansion of TE copies and evolution of host repression in replicate laboratory populations reared at different temperatures. We observed that while populations maintained at high temperatures rapidly go extinct after TE invasion, those maintained at lower temperatures persist, allowing for TE spread and the evolution of host repression. We also surprisingly discovered that invaded populations experienced recurrent insertion of P-elements into a specific long non-coding RNA, lncRNA:CR43651, and that these insertion alleles are segregating at unusually high frequency in experimental populations, indicative of positive selection. We propose that, in addition to driving the evolution of repression, transpositional bursts of invading TEs can drive molecular adaptation.

evolutionary biology↗