Author: Anowarul Islam
Islam, Anowarul, 2025 Metabolic effects of aneuploidy and their relevance to cancer and neurological phenotypes, Flinders University, College of Medicine and Public Health
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Chromosomal instability (CIN), a hallmark of most human solid tumors, causes ongoing chromosomal gains or losses, leading to aneuploidy. Aneuploidy contributes to cancer progression, poor prognosis, and drug resistance. Targeting aneuploidy for cancer treatment requires understanding signaling pathways enabling aneuploid cell survival. Using Drosophila as a model, I investigated transcriptional responses to CIN and identified altered one-carbon metabolism, particularly S-Adenosyl methionine (SAM) pathways. Depleting SAM synthase in CIN cells induced apoptosis, reversible by spermine supplementation. Loss of polyamines heightened reactive oxygen species susceptibility and reduced autophagy, driving CIN cell death, suggesting polyamine inhibition as a therapeutic strategy. Additionally, I modeled neuronal aneuploidy in Drosophila, linking Mad2 depletion in GABAergic neurons to increased aneuploidy, cell death, and seizure phenotypes, mitigated by antioxidants. Finally, we developed Drosophila lines expressing human KCNT1 epilepsy mutations, demonstrating seizure phenotypes modifiable by cannabidiol. This establishes Drosophila as a model to study CIN-related diseases and KCNT1 epilepsy.
Keywords: Aneuploidy, Chromosomal Instability, Polyamines, S-Adenosyl methionine, Mad2, Drosophila, One carbon metabolism, Neurological phenotypes, KCNT1, Epilepsy.
Subject: Medicine thesis
Thesis type: Doctor of Philosophy
Completed: 2025
School: College of Medicine and Public Health
Supervisor: Dr Stephen Gregory