Cyclin E overexpression in the Drosophila accessory gland induces tissue dysplasia

Abstract

The regulation of the cell division cycle is governed by a complex network of factors that together ensure that growing or proliferating cells maintain a stable genome. Defects in this system can lead to genomic instability that can affect tissue homeostasis and thus compromise human health. Variations in ploidy and cell heterogeneity are observed frequently in human cancers. Here, we examine the consequences of upregulating the cell cycle regulator Cyclin E in the Drosophila melanogaster male accessory gland. The accessory gland is the functional analog of the human prostate. This organ is composed of a postmitotic epithelium that is emerging as a powerful in vivo system for modelling different aspects of tumor initiation and progression. We show that Cyclin E upregulation in this model is sufficient to drive tissue dysplasia. Cyclin E overexpression drives endoreplication and affects DNA integrity, which results in heterogeneous nuclear and cellular composition and variable degrees of DNA damage. We present evidence showing that, despite the presence of genotoxic stress, those cells are resistant to apoptosis and thus defective cells are not eliminated from the tissue. We also show that Cyclin E-expressing cells in the accessory gland display mitochondrial DNA aggregates that colocalize with Cyclin E protein. Together, the findings presented here show that Cyclin E upregulation in postmitotic cells of the accessory gland organ causes cellular defects such as genomic instability and mitochondrial defects, eventually leading to tissue dysplasia. This study highlights novel mechanisms by which Cyclin E might contribute to disease initiation and progression.

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

“…Under normal conditions, we observe a low level of main cells (<1% per day) continuing to endocycle, generating a small population of cells with two 16C nuclei (32C total cellular DNA content), with most adult accessory gland epithelial cells in a long-term quiescent state by a few hours post-eclosion (Box et al, 2024). Additional endocycles can be driven in main cells by expression of positive cell cycle regulators such as CyclinD/Cdk4 or Cyclin E (Box et al, 2024; Molano-Fernandez et al, 2022), but in these instances, the Gal4 driver used expresses prior to eclosion. To test whether expression of positive cell cycle regulators could induce cell cycle re-entry in the quiescent adult gland, we overexpressed the Drosophila activator E2F complex, E2F1 and DP (hereafter referred to as E2F), a known driver of the endocycle (Zielke et al, 2011), or Drosophila Myc, a pro-growth regulator that promotes cell cycle entry and endocycling (Pierce et al, 2004).…”

Cholesterol Dietary Intake and Tumor Cell Homeostasis Drive Early Epithelial Tumorigenesis: A Potential Modelization of Early Prostate Tumorigenesis

“…Indeed, drosophila represents a strong model for deciphering mechanisms related to epithelial cancers, such as lung or colon cancer [ 25 , 26 ]. The accessory gland itself represents a functional equivalent of a prostatic acinus [ 27 , 28 , 29 , 30 , 31 ], and in the last few years, it has been used as a model to decipher molecular signatures and molecular mechanisms related to prostate cancer [ 24 , 32 , 33 , 34 , 35 , 36 ]. Furthermore, there is a strong conservation of cholesterol’s role and metabolism in this insect [ 37 , 38 , 39 ].…”

Editorial: Regulation and coordination of the different DNA damage responses and their role in tissue homeostasis maintenance

“…Although the roles of Cyclin E in normal proliferating cells have been extensively studied, the implications of Cyclin E deregulation in non-proliferating tissues remain poorly understood. In a study presented in this Research Topic, Molano-Fernández and colleagues use the accessory gland of Drosophila as an in vivo model to study the consequences of Cyclin E upregulation in non-proliferating cells ( Molano-Fernández et al, 2023 ). The accessory gland of the fruit fly is the functional orthologue of the human prostate and is emerging as a useful platform to model different aspects related to prostate cancer ( Rambur et al, 2021 ).…”