Deciphering mechanical cues in the microenvironment: from non-malignant settings to tumor progression

Biomarker Research, Journal Year: 2025, Volume and Issue: 13(1)

Published: Jan. 23, 2025

The tumor microenvironment functions as a dynamic and intricate ecosystem, comprising diverse array of cellular non-cellular components that precisely orchestrate pivotal behaviors, including invasion, metastasis, drug resistance. While unraveling the interplay between behaviors represents tremendous challenge, recent research illuminates crucial biological phenomenon known mechanotransduction. Within microenvironment, mechanical cues like tensile stress, shear stiffness play role by activating mechanosensitive effectors such PIEZO proteins, integrins, Yes-associated protein. This activation initiates cascades intrinsic signaling pathways, effectively linking physical properties tissues to their physiological pathophysiological processes morphogenesis, regeneration, immunity. mechanistic insight offers novel perspective on how within impact behaviors. intricacies are yet be fully elucidated, it exhibits distinct attributes from non-malignant tissues, elevated solid stresses, interstitial hypertension, augmented matrix stiffness, enhanced viscoelasticity. These traits exert notable influences progression treatment responses, enriching our comprehension multifaceted nature microenvironment. Through this innovative review, we aim provide new lens decipher contexts, broadening knowledge these factors promote or inhibit thus offering valuable insights identify potential targets for anti-tumor strategies.

Language: Английский

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Large-scale deorphanization of Nematostella vectensis neuropeptide G protein-coupled receptors supports the independent expansion of bilaterian and cnidarian peptidergic systems

eLife, Journal Year: 2024, Volume and Issue: 12

Published: May 10, 2024

Neuropeptides are ancient signaling molecules in animals but only few peptide receptors known outside bilaterians. Cnidarians possess a large number of G protein-coupled (GPCRs) – the most common bilaterian neuropeptides these remain orphan with no ligands. We searched for sea anemone Nematostella vectensis and created library 64 peptides derived from 33 precursors. In large-scale pharmacological screen 161 N. GPCRs, we identified 31 specifically activated by 1 to 3 14 peptides. Mapping GPCR neuropeptide expression single-cell sequencing data revealed how cnidarian tissues extensively connected multilayer peptidergic networks. Phylogenetic analysis direct orthology systems supports independent expansion cnidarians ancestral peptide-receptor pairs.

Language: Английский

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A conserved peptide-binding pocket in HyNaC/ASIC ion channels

Proceedings of the National Academy of Sciences, Journal Year: 2024, Volume and Issue: 121(41)

Published: Oct. 4, 2024

The only known peptide-gated ion channels—FaNaCs/WaNaCs and HyNaCs—belong to different clades of the DEG/ENaC family. FaNaCs are activated by short neuropeptide FMRFamide, HyNaCs Hydra RFamides, which not evolutionarily related FMRFamide. FMRFamide-binding site in was recently identified a cleft atop large extracellular domain. However, this is conserved HyNaCs. Here, we combined molecular modeling site-directed mutagenesis putative binding pocket for Hydra-RFamides domain heterotrimeric HyNaC2/3/5. This localizes one three subunit interfaces, indicating that trimeric channel binds single peptide ligand. We engineered an unnatural amino acid at entrance, allowed covalent tethering RFamide channel, thereby trapping open conformation. same region as acidic acid-sensing channels (ASICs), ligands. less acidic, both electrostatic hydrophobic interactions contribute binding. Collectively, our results reveal ligand-binding ASICs indicate independent evolution peptide-binding cavities two subgroups channels.

Language: Английский

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Large-scale deorphanization of Nematostella vectensis neuropeptide GPCRs supports the independent expansion of bilaterian and cnidarian peptidergic systems

Published: April 8, 2024

Neuropeptides are ancient signaling molecules in animals but only few peptide receptors known outside bilaterians. Cnidarians possess a large number of G protein-coupled (GPCRs) – the most common bilaterian neuropeptides these remain orphan with no ligands. We searched for sea anemone Nematostella vectensis and created library 64 peptides derived from 33 precursors. In large-scale pharmacological screen 161 N. GPCRs, we identified 31 specifically activated by one 14 peptides. Mapping GPCR neuropeptide expression to single-cell sequencing data revealed how cnidarian tissues extensively wired multilayer peptidergic networks. Phylogenetic analysis direct orthology systems supports independent expansion cnidarians ancestral peptide-receptor pairs.

Language: Английский

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Large-scale deorphanization of Nematostella vectensis neuropeptide G protein-coupled receptors supports the independent expansion of bilaterian and cnidarian peptidergic systems

eLife, Journal Year: 2023, Volume and Issue: 12

Published: Sept. 29, 2023

Neuropeptides are ancient signaling molecules in animals but only few peptide receptors known outside bilaterians. Cnidarians possess a large number of G protein-coupled (GPCRs) – the most common bilaterian neuropeptides these remain orphan with no ligands. We searched for sea anemone Nematostella vectensis and created library 64 peptides derived from 33 precursors. In large-scale pharmacological screen 161 N. GPCRs, we identified 31 specifically activated by 1 to 3 14 peptides. Mapping GPCR neuropeptide expression single-cell sequencing data revealed how cnidarian tissues extensively connected multilayer peptidergic networks. Phylogenetic analysis direct orthology systems supports independent expansion cnidarians ancestral peptide-receptor pairs.

Language: Английский

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Aromatic amino acids in the finger domain of the FMRFamide-gated Na$$^+$$ channel are involved in the FMRFamide recognition and the activation

Pflügers Archiv - European Journal of Physiology, Journal Year: 2023, Volume and Issue: 475(8), P. 975 - 993

Published: June 8, 2023

Language: Английский

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Aromatic amino acids in the finger domain of the FMRFamide-gated Na⁺channel are involved in the FMRFamide recognition and the activation

bioRxiv (Cold Spring Harbor Laboratory), Journal Year: 2023, Volume and Issue: unknown

Published: Feb. 3, 2023

Abstract FMRFamide-gated Na + channel (FaNaC) is a member of the DEG/ENaC family and activated by neuropeptide, FMRFamide. Structural information about FMRFamide-dependent gating is, however, still elusive. Because two phenylalanines FMRFamide are essential for activation FaNaC, we hypothesized that aromatic-aromatic interaction between FaNaC critical recognition and/or gating. Here, focused on eight conserved aromatic residues in finger domain FaNaCs tested our hypothesis mutagenic analysis silico docking simulations The mutation reduced potency, extent which were dependent mutated position, suggesting more or less involved activation. kinetics currents also modified substantially some mutants. revealed Collectively, results suggest important determinants ligand FaNaC.

Language: Английский

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Large-scale deorphanization of Nematostella vectensis neuropeptide GPCRs supports the independent expansion of bilaterian and cnidarian peptidergic systems

Published: Sept. 29, 2023

Neuropeptides are ancient signaling molecules in animals but only few peptide receptors known outside bilaterians. Cnidarians possess a large number of G protein-coupled (GPCRs) – the most common bilaterian neuropeptides these remain orphan with no ligands. We searched for sea anemone Nematostella vectensis and created library 64 peptides derived from 33 precursors. In large-scale pharmacological screen 161 N. GPCRs, we identified 31 specifically activated by one 14 peptides. Mapping GPCR neuropeptide expression to single-cell sequencing data revealed how cnidarian tissues extensively wired multilayer peptidergic networks. Phylogenetic analysis direct orthology systems supports independent expansion cnidarians ancestral peptide-receptor pairs.

Language: Английский

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Ion channels and transporters keep ideas flowing

The Journal of Physiology, Journal Year: 2023, Volume and Issue: 601(9), P. 1517 - 1519

Published: April 3, 2023

In biological membranes, channels and transporters underlie essential processes that both mediate impact crucial communications between the intracellular extracellular milieus. Their functional impairment disrupts cellular signalling homeostasis, ultimately translating into systemic dysfunction disease. Similarly, disrupted function befell collective research endeavour with onset of coronavirus disease 2019 pandemic its imposition isolation. For most academic researchers, this effectively ceased not only wet-bench experimentation required to collect data, but also face-to-face exchange knowledge. Although information famine challenged researchers at all stages, effects isolation on junior investigators carried particularly damaging potential. The virtual Themed Meeting, ‘New Roles for Ion Channels Transporters in Health Disease’, was conceived as a means sustain community keep it strong. By bridging gap imposed by social isolation, meeting created forum attendees continue learning from–and be inspired by–colleagues near far. Perhaps more importantly, enthusiastic reception revealed underscored intangible benefit provided from feeling part dynamic community. With Special Issue, we leverage momentum gained Meeting. It offers symposium reviews topical pertinent theme. This issue comprises primary papers emerging groups settling back experimental mode–the products inspiration, renewed resolve tested resilience. an insightful review, Margarida Amaral reflects strategic patterns used generating recent body cystic fibrosis (CF), resulting impaired transmembrane conductance regulator (CFTR) function. relative merits emergent ‘omics’-based approaches (transcriptomics, proteomics, genomics interactomics) are weighed against hypothesis-driven driving rational drug design, well contrasting high-throughput screening identify pharmacotherapies (Amaral, 2023). doing so, based targeting CFTR, rescuing fluid secretion defect associated CF identifying alternative Cl− transport pathways. Thus, example provides object lesson strategies tackling diverse questions. contrast CFTR disease, aberrantly enhanced activity characterizes certain cancers. case gastrointestinal cancers, human ether-à-go-go related gene 1 (hERG1; KV11.1) K+ can drive tumour progression canonical non-canonical means. Arcangeli & colleagues (2023) discuss how association hERG1 β1-integrin subunit recruit membrane receptors, additional ion i.e. Na+/H+ exchanger (NHE1) neonatal form voltage-dependent Na+ channel (nNaV1.5), adhesion molecules. macromolecular complexes promotes cancer (Arcangeli et al., Interestingly, overexpressed KV11 capable conferring resonance potential oscillations (Matsuoka 2021). begs provocative question: do modulate within complexes? Leslie Brackenbury explore importance homeostasis breast tumours. model interweaves actions Na+/K+-ATPase, NHE1, Na+–HCO3− cotransporter (NBCn1), Na+-coupled glucose amino acid transporters, epithelial (ENaC), voltage-gated sodium (i.e. NaV1.5). exception raise Na+. Moreover, NHE1 NBCn1 concomitantly acidify pH. Taken together, explain observations high concentrations low pH tumours (Leslie Brackenbury, systematic Kaulich coworkers broadly cover topic degenerin (DEG)/ENaCs. review bridges work arising genetic electrophysiological approaches, highlighting roles DEG/ENaCs manifold modes sensation, addition their therapeutic targets (Kaulich, Grundy Stephan Gründer recounts his presentation, providing detailed treatment structural basis diversity neuropeptide gating invertebrate DEG/ENaC family members (Gründer 2022). he presents evidence demonstrating modulation, rather than gating, distinct regions vertebrate acid-sensing (ASICs). process likely involves stabilization either open or closed states. Emergent insights hold implications understanding endogenous neuropeptides (including opioid endorphins, such dynorphins) influence physiological via ASIC channels. paper focusing further DEG/ENaCs, Kaulich, McCubbin al. report Caenorhabditis elegans members. These authors leveraged automated voltage-clamp screening, comprehensively profiling sensitivity members, novel acid-activated acid-inhibited Obergrussberger (2022) recently demonstrated amenability other specifically ASIC1, high-throughput, patch-clamp (APC) recording. Applying knowledge discussed (2022), these capabilities enable pharmacology, gain modulation kinetics comprehensive panels neuropeptides. Summarily, ample opportunities understand properties enabling them behave successful sensors throughout animal kingdom. Endogenous metabolic byproducts regulate transporter activity. Combining molecular docking Rosenbaum laboratory transient receptor vallinoid 4 (TRPV4) cation single-channel probability lysophosphotidylcholine (LPC) metabolite, lysophosphotidic (LPA) (Benitez-Angeles TRPV4 expression epithelial, smooth muscle endothelial tissues organs skin lungs, suggests contributions LPC LPA tissue, organ whole-animal airways, proteins play key mediating host responses airborne stimuli, summarized Hollenhorst Krasteva-Christ (2023). Within respiratory tract, stimuli metabolites signal immune system bitter taste receptors specific cell types mouse upper lower airways (Hollenhorst Krasteva-Christ, initiating inflammatory responses, signals engage numerous two pore domain (K2P) Trpm5 channels), enhancing mucociliary clearance defense mechanisms. Insight many Piezo1, mechanosensitive gated forces pressure tension, is rapidly accumulating. eye, Piezo1 trabecular meshwork cells sensing intraocular regulating promoting outflow aqueous humour. Its role aetiology glaucoma, characterized inappropriate development pressure, unfolding steadily (Yarishkin our Barnett share discovery has functions very different namely myometrium. There, modulated protein kinase A/AKT/endothelial nitric oxide synthase-mediated paracrine microvascular endothelium uterine muscle, thereby ensuring quiescence during gestation. noteworthy less expressed myometrium women experiencing preterm labour. studies therefore reveal therapies mitigate condition extenuating consequences (Barnett To complement insights, accompanying Journal Club article (Majhi 2023) concisely thoroughly considers study Finally, surveying included note much what now known about arises studies. Such greatly readily available sequence drawn public databases. resources offer tempting shortcuts (such fragment synthesis) ‘old school’ cloning even PCR reverse-transcribed complementary DNA. However, treasure trove Pandora's box. convenient, construction plasmids directly synthesis using extracted genome sequencing unleash trouble downstream application data interpretation, Maxeiner pithy shares problems uninitiated might encounter, section subtitled ‘How avoid nasty surprises’ walks reader through avert disaster. Given sheer volume investigations reliant expression, cautious rigorous researcher would heed advice offered. collection articles maps potentially fruitful directions moving forwards equally impactful contexts. What physiological, pathophysiological environmental effector machinery? How does machinery scales, best each these? use treat disease? else learn omics-driven research? picture emerges taking context? We will know eventually, if strong ideas flowing. Please note: publisher responsible content functionality any supporting supplied authors. Any queries (other missing content) should directed corresponding author article. None. M.M.: Conception design work; Drafting revising critically important intellectual content; Final approval version published; Agreement accountable aspects P.F.: work.

Language: Английский

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Large-scale deorphanization ofNematostella vectensisneuropeptide GPCRs supports the independent expansion of bilaterian and cnidarian peptidergic systems

bioRxiv (Cold Spring Harbor Laboratory), Journal Year: 2023, Volume and Issue: unknown

Published: July 3, 2023

Abstract Neuropeptides are ancient signaling molecules in animals but only few peptide receptors known outside bilaterians. Cnidarians possess a large number of G protein-coupled (GPCRs) – the most common bilaterian neuropeptides these remain orphan with no ligands. We searched for sea anemone Nematostella vectensis and created library 64 peptides derived from 33 precursors. In large-scale pharmacological screen 161 N. GPCRs, we identified 31 specifically activated by one 14 peptides. Mapping GPCR neuropeptide expression to single-cell sequencing data revealed how cnidarian tissues extensively wired multilayer peptidergic networks. Phylogenetic analysis direct orthology systems supports independent expansion cnidarians ancestral peptide-receptor pairs.

Language: Английский

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