The Drosophila Accessory Gland: A Unique Model for Studying Cellular and Molecular Bases of Polyploid Tumors

Abstract

The mammalian prostate, along with the seminal vesicles, functions to produce the seminal fluid that enhances sperm viability, which is vital for fertility. Prostate biology has been a topic of extensive biomedical research due to the high prevalence of prostate cancer in men over 65 years of age. Significant advancements have been made in the initial treatment of the disease. However, gaining insights into the mechanisms by which cancer cells evade treatment and lead to recurrence remains a primary goal in the research field. The adult male Drosophila accessory gland is a secretory epithelial tissue involved in the production of seminal fluid. This organ serves functions analogous to the mammalian prostate. The mammalian prostate and male accessory gland in Drosophila have significant differences, however, and the secretory cells within the Drosophila organ are unusual in that they are bi-nucleate and polyploid. This means that each cell contains two nuclei, and each nucleus contains multiple copies of the genome, in contrast to the typical two copies found in most diploid animal cells, including those in the human prostate. Despite these differences, my research findings suggest that the Drosophila male accessory gland shares extensive biology with the mammalian prostate. In Chapter 2 of this thesis I examine the degree of molecular similarity between these tissues. I accomplish this by comparing gene expression similarities between the mouse prostate and the Drosophila adult male accessory gland through a cross-species comparison of single-cell transcriptional profiles. This research demonstrates a significant transcriptomic resemblance between the primary epithelial cells of Drosophila's prostate-like accessory gland main cells and the basal epithelial cells of the mammalian prostate. A total of 44 conserved transcription factors were identified within the shared transcriptional signature between Drosophila main cells and mammalian basal cells. This evidence supports the idea that fundamental transcriptional programs crucial for prostate gland function and development are conserved across species, despite their morphological differences and evolutionary distances. In Chapter 3, by driving Drosophila versions of oncogenes expressed in prostate cancer, we model key features of prostate tumorigenesis, such as disrupted epithelial polarity, apical invasion, basal extrusion, hyperplasia, and compromised differentiation, in the absence of mitotic cell proliferation. We find that activation of oncogenes in postmitotic cells activate a network of tumorigenesis and wound-response genes, that lead to cellular hypertrophy resembling that seen in human poly-aneuploid prostate cancer cells. This suggests that the adult Drosophila male accessory gland can be used to study aspects of prostate tumorigenesis despite its postmitotic state. My studies suggest a potential for deep homology in prostate signaling pathways across invertebrates and vertebrates, indicating that fundamental regulatory mechanisms for these tissues may be conserved across substantial evolutionary distances.