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

---

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

---

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

eLife, Journal Year: 2022, Volume and Issue: 11

Published: Nov. 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.

Language: Английский

---

The Notch Signaling Pathway: Mechanistic Insights in Health and Disease

Engineering, Journal Year: 2023, Volume and Issue: 34, P. 212 - 232

Published: Dec. 12, 2023

The Notch signaling pathway is evolutionarily conserved across metazoan species and plays key roles in many physiological processes. receptor activated by two families of canonical ligands (Delta Serrate/Jagged) where both receptors are single-pass transmembrane proteins usually with large extracellular domains, relative to their intracellular portions. Upon interaction the core binding regions, presented on opposing cell surfaces, formation receptor/ligand complex initiates force-mediated proteolysis, ultimately releasing transcriptionally-active domain. This review focuses structural features complex, role post-translational modifications tuning this contribution membrane ligand function, insights from acquired genetic diseases.

Language: Английский

---

Rounding up the Usual Suspects: Assessing Yorkie, AP-1, and Stat Coactivation in Tumorigenesis

International Journal of Molecular Sciences, Journal Year: 2020, Volume and Issue: 21(13), P. 4580 - 4580

Published: June 27, 2020

Can hyperactivation of a few key signaling effectors be the underlying reason for majority epithelial cancers despite different driver mutations? Here, to address this question, we use Drosophila model, which allows analysis gene expression from tumors with known initiating mutations. Furthermore, its simplified pathways have numerous well characterized targets can as pathway readouts. In tumor models, changes in activities three pathways, Jun N-terminal Kinase (JNK), Janus Kinase/Signal Transducer and Activator Transcription (JAK/STAT), Hippo, mediated by AP-1 factors, Stat92E, Yorkie, are reported frequently. We hypothesized may indicate that these commonly deregulated tumors. To assess this, mined available transcriptomic data evaluated activity levels eight various models. Indeed, at least two out our suspects contribute development all cancer models assessed, mutations or tissues origin. Surprisingly, found Notch is also globally activated examined. propose four JNK, JAK/STAT, Notch, paid special attention assayed systematically existing newly developed

Language: Английский

---

Shared enhancer gene regulatory networks between wound and oncogenic programs

bioRxiv (Cold Spring Harbor Laboratory), Journal Year: 2022, Volume and Issue: unknown

Published: June 19, 2022

Abstract 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 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 ras V12 scrib -/- eye disc. We used single-cell multiome profiling derive enhancer Gene Regulatory Networks (eGRNs) integrating chromatin accessibility gene 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. on other hand, signatures simultaneously within same cell. Our eGRNs resource offers an in-depth characterisation senescence markers, together new perspective shared acting oncogenesis.

Language: Английский

---

Decoding the mechanism of vascular morphogenesis to explore future prospects in targeted tumor therapy

Medical Oncology, Journal Year: 2022, Volume and Issue: 39(11)

Published: Aug. 29, 2022

Language: Английский

---

Oncogenic signaling in the adult Drosophila prostate-like accessory gland leads to activation of a conserved pro-tumorigenic program, in the absence of proliferation.

bioRxiv (Cold Spring Harbor Laboratory), Journal Year: 2024, Volume and Issue: unknown

Published: May 12, 2024

Abstract Drosophila models for tumorigenesis and metastasis have revealed conserved mechanisms of signaling that are also involved in mammalian cancer. Many these use the proliferating tissues larval stages development, when highly mitotically active, or stem cells abundant. Fewer adult animals to initiate tumor formation many largely terminally differentiated postmitotic. The accessory glands prostate-like a model some aspects prostate using this tissue has been explored. In model, oncogenic was induced during proliferative stage gland raising question how activity would impact postmitotic tissue. Here, we show leads activation pro-tumorigenic program, similar observed mitotic tissues, but absence proliferation. Oncogenic hyperplasia with nuclear anaplasia aneuploidy through endoreduplication, which increases polyploidy occasionally results non-mitotic neoplastic-like extrusions. We compare gene expression changes our endocycling cancer by chemotherapy, potentially mediate recurrence after treatment. Similar pathways activated cells, suggesting provide useful progression do not involve cellular

Language: Английский

---

Le modèle drosophile et la recherche en cancérologie

Bulletin du Cancer, Journal Year: 2024, Volume and Issue: 111(9), P. 880 - 892

Published: July 2, 2024

Language: Английский

---

Natural variations of aging of cardiac performance in Drosophila identifies a central function for the PAR domain bZIP transcription factor Pdp1/dHLF in cardiac senescence

bioRxiv (Cold Spring Harbor Laboratory), Journal Year: 2024, Volume and Issue: unknown

Published: Oct. 1, 2024

Summary The identification of genetic factors influencing cardiac senescence in natural populations is central to our understanding aging and identify the etiology associated disorders human populations. However, underpinning complex traits almost impossible, due infeasibility control background gene-environment interactions. Drosophila has striking similarities with humans, highlighting conserved nature for organisms a heart. Leveraging on large collection inbred lines from Genetic Reference Panel (DGRP), we provide an accurate analysis population flies. This permitted discovery unprecedented number variants genes significantly variation aging. We focused function PAR domain bZIP transcription factor Pdp1 which several were found multiple functional traits. demonstrated that cell autonomously plays role might do so by regulating mitochondria homeostasis. Overall, work provides unique resource regarding genetics population.

Language: Английский

---