Activation of a Src-JNK pathway in unscheduled endocycling cells of the Drosophila wing disc induces a chronic wounding response

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

Published: March 13, 2025

Abstract The endocycle is a specialized cell cycle during which cells undergo repeated G / S phases to replicate DNA without division, leading large polyploid cells. transition from mitotic an can be triggered by various stresses, results in unscheduled, or induced endocycling (iECs). While iECs beneficial for wound healing, they also detrimental impairing tissue growth promoting cancer. However, the regulation of and its role remain poorly understood. Using Drosophila wing disc as model, we previously demonstrated that iEC arrested through Jun N-Terminal Kinase (JNK)-dependent, reversible senescence-like response. it remains unclear how JNK activated impact overall structure. In this study, performed genetic screen identified Src42A-Shark-Slpr pathway upstream regulator iECs, their arrest. We found tissues recognize wounds, releasing wound-related signals induce JNK-dependent developmental delay. Similar closure, response triggers Src-JNK-mediated actomyosin remodeling, yet persist rather than being eliminated. Our findings suggest shares key signaling cytoskeletal regulatory mechanisms with healing dorsal process embryogenesis. because are retained within tissue, create unique system may serve model studying chronic wounds tumor progression. Article summary effects unscheduled endocycles on unclear. To investigate this, used switch analyzed responses at both structure levels. Surprisingly, recognized activating regeneration remodeling these resist apoptosis, cleared. This persistence disrupts normal revealing similarities between wounds. has potential novel tumorigenesis.

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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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

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Wnt signaling modulates the response to DNA damage in the Drosophila wing imaginal disc by regulating the EGFR pathway

PLoS Biology, Journal Year: 2024, Volume and Issue: 22(7), P. e3002547 - e3002547

Published: July 24, 2024

Despite the deep conservation of DNA damage response (DDR) pathway, cells in different contexts vary widely their susceptibility to and propensity undergo apoptosis as a result genomic lesions. One cell signaling pathways implicated modulating DDR is highly conserved Wnt which known promote resistance caused by ionizing radiation variety human cancers. However, mechanisms linking signal transduction remain unclear. Here, we use genetically encoded system Drosophila reliably induce consistent levels vivo, demonstrate that canonical wing imaginal disc buffers against face double-strand breaks. We show Wg, primary ligand Drosophila, activates epidermal growth factor receptor (EGFR) via ligand-processing protease Rhomboid, which, turn, modulates Chk2-, p53-, E2F1-dependent manner. These studies provide mechanistic insight into modulation EGFR vivo proliferative tissue. Furthermore, they reveal how patterning functions are coupled with prosurvival, antiapoptotic activities, thereby facilitating developmental robustness damage.

Language: Английский

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