Shared enhancer gene regulatory networks between wound and oncogenic programs

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

Published: May 3, 2023

Wound response programs are often activated during neoplastic growth in tumors. In both wound repair and tumor growth, cells respond to acute stress balance the activation of multiple programs, including apoptosis, proliferation, cell migration. Central those responses JNK/MAPK JAK/STAT signaling pathways. Yet, what extent these cascades interact at cis-regulatory level how they orchestrate different regulatory phenotypic is still unclear. Here, we aim characterize states that emerge cooperate response, using Drosophila melanogaster wing disc as a model system, compare with cancer induced by rasV12scrib-/- eye disc. We used single-cell multiome profiling derive enhancer gene networks (eGRNs) integrating chromatin accessibility expression signals. identify 'proliferative' eGRN, active majority wounded controlled AP-1 STAT. smaller, but distinct population cells, 'senescent' eGRN driven C/EBP-like transcription factors (Irbp18, Xrp1, Slow border, Vrille) Scalloped. These two signatures found be levels. Our eGRNs resource offers an in-depth characterization senescence markers, together new perspective on shared acting oncogenesis.

Language: Английский

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The ctenophore Mnemiopsis leidyi deploys a rapid injury response dating back to the last common animal ancestor

Communications Biology, Journal Year: 2024, Volume and Issue: 7(1)

Published: Feb. 19, 2024

Abstract Regenerative potential is widespread but unevenly distributed across animals. However, our understanding of the molecular mechanisms underlying regenerative processes limited to a handful model organisms, restricting robust comparative analyses. Here, we conduct time course RNA-seq during whole body regeneration in Mnemiopsis leidyi (Ctenophora) uncover gene expression changes that correspond with key events timeline this species. We identified several genes highly enriched dataset beginning as early 10 minutes after surgical bisection including transcription factors timepoints, peptidases middle and cytoskeletal later timepoints. validated response by mount situ hybridization, showing these exhibited high tissues surrounding wound site. These exhibit pattern transient upregulation seen variety other suggesting they may be initiators an ancient regulatory network linking healing initiation response.

Language: Английский

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Macrophages Facilitate Interclonal Cooperation-Induced Tumor Malignancy by Hijacking the Innate Immune System

Published: Jan. 1, 2025

Tumor heterogeneity is a common hallmark of cancer and considered major cause treatment failure relapse, yet it remains poorly understood how various types cells communicate within the tumor microenvironment to regulate progression in vivo. Here we establish novel model eye epithelium Drosophila melanogaster dissect vivo mechanisms underlying intercellular communication by combining sophisticated genetic techniques with single-cell RNA sequencing (scRNA-seq). Our results demonstrate that targeted mutation tricellular junction protein M6 surrounding RasV12 benign tumors promotes their malignant transformation. Mechanistically, loss activates JNK signaling, which propagates tumors, leading an increased recruitment macrophages site. Subsequently, tumor-associated secrete Spatzle (Spz) ligand activate Toll receptor tumors. Ultimately, pathway activation synergizes promote its transformation inactivating Hippo pathway. In summary, our study elucidates complex interplay among genetically distinct oncogenic cells, as well between macrophages, shedding light on exploit ancient innate immune system coordinate heterogeneity-mediated progression.

Language: Английский

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Single-cell transcriptomics of X-ray irradiated Drosophila wing discs reveals heterogeneity related to cell-cycle status and cell location

Published: April 22, 2025

Even seemingly homogeneous populations of cells can express phenotypic diversity in response to environmental changes. Thus, X-ray irradiation tissues composed diverse cell types have complex outcomes. We used single-cell RNA-sequencing study the effects radiation on Drosophila wing imaginal disc, a relatively simple tissue mostly epithelial cells. Transcriptomic clustering collected from disc generates clusters that are mainly grouped based proximodistal location. To quantify heterogeneity gene expression among clusters, we adapted metric market concentration, Herfindahl-Hirschman Index. Genes involved DNA damage repair, defense against reactive oxygen species, cycle progression, and apoptosis expressed uniformly. In contrast, genes encoding subset ligands, notably cytokines activate JAK/STAT pathway, some transcription factors including Ets21C , previously implicated regeneration, several signaling proteins more regionally. Though radiation-responsive factor p53 is uniformly regionally-induced still require function, indicating regional radiation-induced combine regulate their expression. also examined within regions using approach A subpopulation cells, characterized by high levels tribbles expression, amplified irradiated discs. Remarkably, this accounts for considerable fraction cellular responses non-uniform even regions. both inter-regional intra-regional important features radiation.

Language: Английский

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Single-cell transcriptomics of X-ray irradiated Drosophila wing discs reveals heterogeneity related to cell-cycle status and cell location

Published: April 22, 2025

Even seemingly homogeneous populations of cells can express phenotypic diversity in response to environmental changes. Thus, X-ray irradiation tissues composed diverse cell types have complex outcomes. We used single-cell RNA-sequencing study the effects radiation on Drosophila wing imaginal disc, a relatively simple tissue mostly epithelial cells. Transcriptomic clustering collected from disc generates clusters that are mainly grouped based proximodistal location. To quantify heterogeneity gene expression among clusters, we adapted metric market concentration, Herfindahl-Hirschman Index. Genes involved DNA damage repair, defense against reactive oxygen species, cycle progression, and apoptosis expressed uniformly. In contrast, genes encoding subset ligands, notably cytokines activate JAK/STAT pathway, some transcription factors including Ets21C , previously implicated regeneration, several signaling proteins more regionally. Though radiation-responsive factor p53 is uniformly regionally-induced still require function, indicating regional radiation-induced combine regulate their expression. also examined within regions using approach A subpopulation cells, characterized by high levels tribbles expression, amplified irradiated discs. Remarkably, this accounts for considerable fraction cellular responses non-uniform even regions. both inter-regional intra-regional important features radiation.

Language: Английский

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Local ecdysone synthesis in a wounded epithelium sustains developmental delay and promotes regeneration in Drosophila

Development, Journal Year: 2024, Volume and Issue: 151(12)

Published: May 22, 2024

Regenerative ability often declines as animals mature past embryonic and juvenile stages, suggesting that regeneration requires redirection of growth pathways promote developmental growth. Intriguingly, the Drosophila larval epithelia require hormone ecdysone (Ec) for but a drop in circulating Ec levels to regenerate. Examining dynamics more closely, we find transcriptional activity Ec-receptor (EcR) drops uninjured regions wing discs, simultaneously rises cells around injury-induced blastema. In parallel, blastema depletion genes encoding biosynthesis enzymes blocks EcR impairs has no effect on wings. We local Ec/EcR signaling is required pupariation delay following injury key regulators upd3 Ets21c respond levels. Collectively, these data indicate induces source within sustains signature necessary tissue repair.

Language: Английский

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Myc and Tor drive growth and cell competition in the regeneration blastema ofDrosophilawing imaginal discs

bioRxiv (Cold Spring Harbor Laboratory), Journal Year: 2025, Volume and Issue: unknown

Published: March 16, 2025

Abstract During the regeneration of injured or lost tissues, blastema serves as a hub for robust growth. Drosophila imaginal discs are genetically tractable and simple model system study organization this regrowth. Key signals that contribute to regenerative growth in these discs, such ROS, Wnt/Wg, JNK, p38, JAK/STAT, Hippo pathway, have been identified. However, detailed exploration spatial regrowth, factors directly drive growth, consequences activating drivers has not undertaken. Here, we find is controlled by transcription factor Myc Tor signaling, which additively proliferation translation blastema. The arranged into concentric zones defined expression, elevated activity, translation. In addition, increased expression innermost zone induced Xrp1-independent cell competition-like death adjacent zones, revealing delicate balance between driving inducing regenerating tissue. Summary statement wing disc characterized factor, signaling Myc-induced competition .

Language: Английский

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Some molecular aspects of larval development in Paralithodes camtschaticus

PLoS ONE, Journal Year: 2025, Volume and Issue: 20(4), P. e0322234 - e0322234

Published: April 29, 2025

The transcriptome of the red king crab, Paralithodes camtschaticus , was sequenced at four developmental stages: zoea I, IV, glaucothoe, and juveniles. Based on our RNA-seq data paired-end reads from 112 libraries obtained by other researchers earlier, assembly for P. that we has proven to be most complete those reported date. An analysis enriched processes different stages shown, some adaptations, e.g., elevated temperature hypoxia, do not appear in early larvae. Thus, it is important maintain optimal conditions normal larval development reduce mortality rates. According results expression profile clustering transcription factor (TF) search, TFs are associated with various organs, metamorphosis, immune responses. provide an additional basis deeper investigation into mechanisms biphasic life cycle decapods can helpful commercial crab stock enhancement programs.

Language: Английский

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Oncogenic signaling in the Drosophila prostate-like accessory gland activates a pro-tumorigenic program in the absence of proliferation

Disease Models & Mechanisms, Journal Year: 2025, Volume and Issue: 18(4)

Published: April 1, 2025

ABSTRACT Drosophila models for tumorigenesis have revealed conserved mechanisms of signaling involved in mammalian cancer. Many these use highly mitotically active tissues. Few adult tissues, when most cells are terminally differentiated and postmitotic. The accessory glands prostate-like a model prostate using this tissue has been explored. In prior model, oncogenic was induced during the proliferative stages gland development, raising question how activity impacts differentiated, postmitotic tissue. Here, we show that leads to activation pro-tumorigenic program, similar mitotic but absence proliferation. our experiments, led hypertrophy with nuclear anaplasia, part through endoreduplication. Oncogene-induced gene expression changes overlapped those polyploid cancer after chemotherapy, which potentially mediate tumor recurrence. Thus, provide useful aspects progression lack cellular

Language: Английский

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Drosophila: a Tale of regeneration with MYC

Frontiers in Cell and Developmental Biology, Journal Year: 2024, Volume and Issue: 12

Published: July 23, 2024

Regeneration is vital for many organisms, enabling them to repair injuries and adapt environmental changes. The mechanisms underlying regeneration are complex involve coordinated events at the cellular molecular levels. Moreover, while some species exhibit remarkable regenerative capabilities, others, like mammals, have limited potential. Central this process regulation of gene expression, among numerous genes involved, MYC emerges as a regulator relevant processes during with roles conserved in several species, including Drosophila . This mini-review aims provide valuable insights into flies, focusing on significant organs where role has been identified: from imaginal discs, regulates cell growth, structure, proliferation, gut, it maintains balance between renewal differentiation stem cells, central nervous system, influences activities neural cells interaction glia neuronal cells. By emphasizing regulated by MYC, its significance controlling mechanisms, we aim offer utility model studying regeneration. unraveling MYC’s function may help translate findings human tissue repair.

Language: Английский

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