A Novel Genetic Platform to Study Intestinal Tumorigenesis in Drosophila

Epithelial tissues rely on the activity of stem cells to sustain their structure and proper functioning. These stem cells are responsible for generating various types of cells, that are essential for the tissue's normal homeostasis, through division and differentiation. In order to ensure precise control over stem cell behavior and the decisions they make regarding cell fate, constant communication through a network of signaling pathways between different cell types is necessary. This delicate network of cell-cell interactions however is frequently disrupted in the face of cancer and the development of tumorigenesis. However, the mechanisms by which these interactions are broken and often co-opted to support tumor growth in different genetic contexts are not yet well understood. To shed light on this phenomenon, we have developed several genetically complex colorectal models utilizing a novel genetic platform named PromoterSwitch. PromoterSwitch allows us to generate large, transformed clones from a small subset of individual adult Drosophila intestinal stem and progenitor cells. By utilizing this platform, we have discovered that genetic alterations commonly found in colon tumors can interfere with the normal process of cell fate determination within the transformed tissue and in neighboring wildtype cells. Furthermore, our research has revealed that transformed enteroendocrine cells, which are a specialized lineage of intestinal hormone-secreting cells, play a crucial role in supporting tumor growth via the regulation of the proliferation of intestinal stem cells through multiple mechanisms that depend on the specific genetic background of the clone. These findings suggest potential vulnerabilities that could be targeted for therapeutic purposes such as enteroendocrine cell differentiation and the hormone Tk, which results showed plays a pivotal role in driving intestinal tumorigenesis. The findings of our work emphasize the importance of developing and investigating disease models that faithfully recapitulate the intricate genetic landscapes observed in human cancer patients in the context of an otherwise healthy epithelial tissue to precisely mimic the initiation and progression of the disease in humans. Our research also showcases the remarkable capacity of Drosophila as a robust model organism for studying genetically complex diseases in a sophisticated manner. By leveraging the close homology and conservation of epithelial tissue and disease-relevant genes and pathways, Drosophila offers unique opportunities to make groundbreaking discoveries with direct implications for human diseases. Overall, our study demonstrates that disruptions in cell fate decisions and the exploitation of enteroendocrine cells are key factors in tumor growth providing a deeper understanding on the cellular heterogeneity and plasticity observed in the disease that could pave the way for the development of new therapeutic strategies aimed at exploiting these mechanisms for effective colorectal cancer treatment.

Grantor dc:publisher

Florida State University

Year dc:date

2023

Contributors dc:contributor

• Quintero Rodriguez, Maria (author)
• Bangi, Erdem (professor directing dissertation)
• Arbeitman, Michelle N. (Michelle Nina) (university representative)
• Dennis, Jonathan Hancock (committee member)
• Zhu, Fanxiu (committee member)
• Irianto, Jerome (committee member)
• Florida State University (degree granting institution)
• College of Arts and Sciences (degree granting college)
• Department of Biological Science (degree granting department)

• Cytology
• Molecular biology
• Oncology

Language dc:language

English

Identifier

fsu:928031
iid: QuinteroRodriguez_fsu_0071E_18192

OAI identifier oai:identifier

oai:diginole.lib.fsu.edu:fsu_928031