Drosophila Accessory Gland: A Complementary In Vivo Model to Bring New Insight to Prostate Cancer

Rambur, Amandine; Vialat, Marine; Beaudoin, Claude; Lours-Calet, Corinne; Lobaccaro, Jean-Marc A.; Baron, Silvère; Morel, Laurence; Joussineau, Cyrille de

doi:10.3390/cells10092387

Cited by 5 publications

(6 citation statements)

References 176 publications

(191 reference statements)

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“…Half of men between 70-80 years of age show histological evidence of malignancy in the prostate (Carter et al, 1990). The Drosophila accessory glands serve reproductive functions analogous to the mammalian prostate, raising the possibility that these tissues in aged adult animals could be useful models for prostate cancer (Corrigan et al, 2014; Ito et al, 2014; Leiblich et al, 2019; Rambur et al, 2020; Rambur et al, 2021; Wilson et al, 2017). The fly reproductive system contains two accessory glands that release seminal fluid components into the Ejaculatory duct, where the seminal vesicles and testes also deposit sperm and additional seminal fluid components (Adams and Wolfner, 2007; Bloch Qazi and Wolfner, 2003; Cridland et al, 2022; Heifetz et al, 2005; Lung et al, 2001; Ravi Ram et al, 2005; Schnakenberg et al, 2012; Wilson et al, 2017).…”

Section: Introductionmentioning

confidence: 99%

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

Church,

Pulianmackal,

Dixon

et al. 2024

Preprint

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

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Section: Introductionmentioning

confidence: 99%

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

Church,

Pulianmackal,

Dixon

et al. 2024

Preprint

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“…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 ].…”

Section: Introductionmentioning

confidence: 99%

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

Vialat,

Baabdaty,

Trousson

et al. 2024

Cancers

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Epidemiological studies point to cholesterol as a possible key factor for both prostate cancer incidence and progression. It could represent a targetable metabolite as the most aggressive tumors also appear to be sensitive to therapies designed to decrease hypercholesterolemia, such as statins. However, it remains unknown whether and how cholesterol, through its dietary uptake and its metabolism, could be important for early tumorigenesis. Oncogene clonal induction in the Drosophila melanogaster accessory gland allows us to reproduce tumorigenesis from initiation to early progression, where tumor cells undergo basal extrusion to form extra-epithelial tumors. Here we show that these tumors accumulate lipids, and especially esterified cholesterol, as in human late carcinogenesis. Interestingly, a high-cholesterol diet has a limited effect on accessory gland tumorigenesis. On the contrary, cell-specific downregulation of cholesterol uptake, intracellular transport, or metabolic response impairs the formation of such tumors. Furthermore, in this context, a high-cholesterol diet suppresses this impairment. Interestingly, expression data from primary prostate cancer tissues indicate an early signature of redirection from cholesterol de novo synthesis to uptake. Taken together, these results reveal that during early tumorigenesis, tumor cells strongly increase their uptake and use of dietary cholesterol to specifically promote the step of basal extrusion. Hence, these results suggest the mechanism by which a reduction in dietary cholesterol could lower the risk and slow down the progression of prostate cancer.

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“…The Drosophila accessory gland contains two types of secretory cells: namely, main cells, the most abundant cell type, and secondary cells, present in the distal tip of this organ ( Supplementary Figure S1 ). Previous analyses have shown that tumorigenesis in both organs, namely the human prostate and the Drosophila accessory gland, can be driven by similar mechanisms ( Ito et al, 2014 ; Wilson et al, 2017 ; Rambur et al, 2020 ; Rambur et al, 2021 ). The accessory gland is emerging as a useful model to study different aspects related to cancer initiation and progression ( Ito et al, 2014 ; Wilson et al, 2017 ; Rambur et al, 2020 ; Rambur et al, 2021 ; Box et al, 2022 ).…”

Section: Introductionmentioning

confidence: 99%

“…Previous analyses have shown that tumorigenesis in both organs, namely the human prostate and the Drosophila accessory gland, can be driven by similar mechanisms ( Ito et al, 2014 ; Wilson et al, 2017 ; Rambur et al, 2020 ; Rambur et al, 2021 ). The accessory gland is emerging as a useful model to study different aspects related to cancer initiation and progression ( Ito et al, 2014 ; Wilson et al, 2017 ; Rambur et al, 2020 ; Rambur et al, 2021 ; Box et al, 2022 ). The adult accessory gland is a postmitotic organ.…”

Section: Introductionmentioning

confidence: 99%

Cyclin E overexpression in the Drosophila accessory gland induces tissue dysplasia

Molano-Fernández

Hickson²,

Herranz³

2023

Front. Cell Dev. Biol.

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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.

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Drosophila Accessory Gland: A Complementary In Vivo Model to Bring New Insight to Prostate Cancer

Cited by 5 publications

References 176 publications

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

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

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

Cyclin E overexpression in the Drosophila accessory gland induces tissue dysplasia

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