Mutual repression between JNK/AP-1 and JAK/STAT stratifies senescent and proliferative cell behaviors during tissue regeneration

PLoS Biology, Год журнала: 2023, Номер 21(5), С. e3001665 - e3001665

Опубликована: Май 30, 2023

Epithelial repair relies on the activation of stress signaling pathways to coordinate tissue repair. Their deregulation is implicated in chronic wound and cancer pathologies. Using TNF-α/Eiger-mediated inflammatory damage Drosophila imaginal discs, we investigate how spatial patterns behaviors arise. We find that Eiger expression, which drives JNK/AP-1 signaling, transiently arrests proliferation cells center associated with a senescence program. This includes production mitogenic ligands Upd family, allows JNK/AP-1-signaling act as paracrine organizers regeneration. Surprisingly, cell-autonomously suppress via Ptp61F Socs36E, both negative regulators JAK/STAT signaling. As suppressed at damage, compensatory occurs by periphery. Mathematical modelling suggests cell-autonomous mutual repression between core regulatory network essential spatially separate into bistable domains distinct cellular tasks. Such stratification for proper repair, coactivation same creates conflicting signals cell cycle progression, leading excess apoptosis senescently stalled organize field. Finally, demonstrate separation senescent proliferative not only upon but also Ras V12 , scrib tumors. Revealing this previously uncharacterized JNK/AP-1, JAK/STAT, has important implications our conceptual understanding pathologies, tumor microenvironments.

Язык: 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, Год журнала: 2025, Номер 18(4)

Опубликована: Апрель 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

Язык: Английский

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RasV12; scrib−/− Tumors: A Cooperative Oncogenesis Model Fueled by Tumor/Host Interactions

International Journal of Molecular Sciences, Год журнала: 2021, Номер 22(16), С. 8873 - 8873

Опубликована: Авг. 18, 2021

The phenomenon of how oncogenes and tumor-suppressor mutations can synergize to promote tumor fitness cancer progression be studied in relatively simple animal model systems such as Drosophila melanogaster. Almost two decades after the landmark discovery cooperative oncogenesis between oncogenic RasV12 loss suppressor scribble flies, this other models have provided new concepts findings biology that has remarkable parallels relevance human cancer. Here we review using RasV12; scrib−/− it contributed our understanding these initial genetic insults cooperate within cell set motion malignant transformation program leading growth through growth, survival proliferation, dismantling cell–cell interactions, degradation basement membrane spreading organs. Recent demonstrated cooperativity goes beyond intrinsic mechanisms interacts with immediate cells microenvironment, immune system systemic organs eventually facilitate progression.

Язык: Английский

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Single-cell transcriptomics identifies Keap1-Nrf2 regulated collective invasion in a Drosophila tumor model

eLife, Год журнала: 2022, Номер 11

Опубликована: Ноя. 2, 2022

Apicobasal cell polarity loss is a founding event in epithelial-mesenchymal transition and epithelial tumorigenesis, yet how pathological links to plasticity remains largely unknown. To understand the mechanisms mediators regulating upon loss, we performed single-cell RNA sequencing of Drosophila ovaries, where inducing polarity-gene l(2)gl-knockdown (Lgl-KD) causes invasive multilayering follicular epithelia. Analyzing integrated Lgl-KD wildtype transcriptomes, discovered cells specific various discernible phenotypes characterized underlying gene expression. A genetic requirement Keap1-Nrf2 signaling promoting multilayer formation was further identified. Ectopic expression Keap1 increased volume delaminated follicle that showed enhanced behavior with significant changes cytoskeleton. Overall, our findings describe comprehensive transcriptome within tumor model at resolution identify previously unappreciated link between early tumorigenesis.In body, most exhibit some form spatial asymmetry: compartments are not evenly distributed, thereby allowing know whether surface on ‘outside’ or ‘inside’ tissue organ. In tissues, which line cavities organs this asymmetry known as apical-basal polarity. Maintaining one main barriers stops cancer from invading other first step metastasis, process through leave their origin spread distant locations body. fruit fly melanogaster, scientists have engineered several tissues stop producing proteins help establish polarity, an effort study earliest steps formation. Unfortunately, these experiments frequently lead rampant making it difficult make more likely become invasive. Therefore, finding does cause aggressive progression necessary address gap knowledge. The layer lining ovaries flies may be such tissue. When lose rather than becoming metastatic spreading organs, they interleave each other, forming tumorous growth only invades into neighboring compartment. Chatterjee et al. used system individual cells. They wanted genes switch off involved human cancers, if so, them control determined when fruit-fly ovary lost turned pattern similar seen both mammalian cancers tumors tissues. One notable observed ovarian activation Keap1/Nrf2 oxidative-stress pathway, normally protects damage caused by excessive oxidation. cells, however, also led invasion collective Interestingly, increase invasiveness polarized specifically scaffolding allows keep shape move: edge leading had greater levels protein called actin, enables protrude compartments. identified new mechanism impacts migratory Insights will pave way for better understanding plays role metastasis.

Язык: Английский

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Metabolic reprogramming in cancer: mechanistic insights from Drosophila

Disease Models & Mechanisms, Год журнала: 2021, Номер 14(7)

Опубликована: Июль 1, 2021

Cancer cells constantly reprogram their metabolism as the disease progresses. However, our understanding of metabolic complexity cancer remains incomplete. Extensive research in fruit fly Drosophila has established numerous tumor models ranging from hyperplasia to neoplasia. These exhibit a broad range profiles and varying nutrient sensitivity. Genetic studies show that tumors can use various alternative strategies, such feedback circuits nutrient-sensing machinery, acquire consolidate distinct profiles. not only provide fresh insights into causes functional relevance reprogramming but also identify vulnerabilities potential targets for therapy. Here, we review conceptual advances derived comparing contrasting models, with particular focus on Warburg effect, mitochondrial metabolism, links between diet cancer.

Язык: Английский

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Mechanisms underlying the cooperation between loss of epithelial polarity and Notch signaling during neoplastic growth in Drosophila

Development, Год журнала: 2022, Номер 149(3)

Опубликована: Янв. 10, 2022

ABSTRACT Aggressive neoplastic growth can be initiated by a limited number of genetic alterations, such as the well-established cooperation between loss cell architecture and hyperactive signaling pathways. However, our understanding how these different alterations interact influence each other remains very incomplete. Using Drosophila paradigms imaginal wing disc epithelial growth, we have monitored changes in Notch pathway activity according to polarity status cells (scrib mutant). We show that scrib mutation impacts direct transcriptional output pathway, without altering global distribution Su(H), Notch-dedicated transcription factor. The Notch-dependent neoplasms require, however, action group factors, similar those previously identified for Ras/scrib neoplasm (namely AP-1, Stat92E, Ftz-F1 basic leucine zipper factors), further suggesting importance this factor network during growth. Finally, work highlights some Notch/scrib specificities, particular role PAR domain-containing target Pdp1

Язык: Английский

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Identification of New, Functionally Relevant Mutations in the Coding Regions of the Human Fos and Jun Proto-Oncogenes in Rheumatoid Arthritis Synovial Tissue

Life, Год журнала: 2020, Номер 11(1), С. 5 - 5

Опубликована: Дек. 23, 2020

In rheumatoid arthritis (RA), the expression of many pro-destructive/pro-inflammatory proteins depends on transcription factor AP-1. Therefore, our aim was to analyze presence and functional relevance mutations in coding regions AP-1 subunits fos jun family peripheral blood (PB) synovial membranes (SM) RA osteoarthritis patients (OA, disease control), as well normal controls (NC). Using non-isotopic RNAse cleavage assay, one known polymorphism (T252C: silent; rs1046117; present RA, OA, NC) three novel germline cfos gene were detected: (i) C361G/A367G: Gln121Glu/Ile123Val, denoted “fos121/123”; only OA sample; (ii) G374A: Arg125Lys, “fos125”; (iii) C217A/G374A: Leu73Met/Arg125Lys, “fos73/125”, latter two exclusively RA. addition, somatic cjun (604–606ΔCAG: ΔGln202, “jun202”; C706T: Pro236Ser, “jun236”; G750A: silent) found SM. Tansgenic fos125 fos73/125 mutants NIH-3T3 cells induced an activation reporter constructs containing either MMP-1 (matrix metalloproteinase) promoter (3- 4-fold, respectively) or a pentameric site (approximately 5-fold). Combined these with wildtype (jun202, jun236) further enhanced construct. Finally, genotyping for functionally relevant 298 288 484 NC samples revealed no association Thus, cfos/cjun may contribute local joint inflammation/destruction selected by altering transactivation capacity complexes.

Язык: Английский

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A Blueprint for Cancer-Related Inflammation and Host Innate Immunity

Cells, Год журнала: 2021, Номер 10(11), С. 3211 - 3211

Опубликована: Ноя. 17, 2021

Both in situ and allograft models of cancer juvenile adult Drosophila melanogaster fruit flies offer a powerful means for unravelling gene networks cancer-host interactions. They can also be used as tools cost-effective drug discovery repurposing. Moreover, modeling emerging tumors makes it possible to address initiating events-a black box research, tackle the innate antitumor immune responses incipient preneoplastic cells recurrent growing tumors, decipher initiation evolution inflammation. These studies serve blueprint more complex organisms help design mechanism-based therapies individualized treatment diseases humans. This review focuses on new discoveries related diverse cancer-related inflammation systemic effects that are so detrimental host.

Язык: Английский

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Transient loss of Polycomb components induces an epigenetic cancer fate

bioRxiv (Cold Spring Harbor Laboratory), Год журнала: 2023, Номер unknown

Опубликована: Янв. 4, 2023

Summary Cell fate depends on genetic, epigenetic and environmental inputs that are interconnected, making it difficult to disentangle their respective contributions cell decisions 1-3 , reprogramming is a major contributor tumor plasticity adaptation 4-6 . Although cancer initiation progression generally associated with the accumulation of somatic mutations 7,8 substantial epigenomic alterations underlie many aspects tumorigenesis susceptibility 9-18 suggesting genetic mechanisms alone may not be sufficient drive malignant transformations 19-23 However, whether purely non-genetic initiate irrespective unknown. Here, we show transient perturbation transcriptional silencing mediated by Polycomb-Group proteins induce an irreversible switch in Drosophila This linked derepression genes can tumorigenesis, including JNK JAK-STAT signalling pathways zfh1 fly homolog ZEB1 oncogene, which necessary driver fate. These data reversible protein levels absence suggest this achieved through inheritance altered fates.

Язык: Английский

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Basic and Translational Models of Cooperative Oncogenesis

International Journal of Molecular Sciences, Год журнала: 2020, Номер 21(16), С. 5919 - 5919

Опубликована: Авг. 18, 2020

n/a

Язык: Английский

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