Elucidating Prostate Cancer Biology Through Integrative Computational Multi-omic Analyses
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Embargo End Date
2028-03-27
ICR Authors
Authors
Gallagher, L
Document Type
Thesis or Dissertation
Date
2025-03-27
Date Accepted
Abstract
in this thesis, I aimed to elucidate the microbial landscape of castration-resistant prostate cancer (CRPC), focusing on novel biomarkers of therapeutic
resistance. We employed metagenomic sequencing of over 200 CRPC patients, alongside in vitro cell Line and ex vivo patient-derived xenograft (POX), models, to investigate microbial biomarkers of progression from hormone-sensitive prostate cancer {HSPC) to CRPC.
Metagenomic sequencing effectively characterised the gut microbiome ofCRPC patients. While microbiome alpha diversity between HSPC and CRPC I remained similar, species-level changes, including an increased abundance of Adlercreutzia equolifaciens, were observed in CRPC. Further, L- 1 citrulline biosynthesis by the microbiota was linked to improved AR -negative prostate cancer cell viability, highlighting its potential role in CRPC i progression. Analysis ofCRPC biopsy samples provided inconclusive evidence for intra-tumour micro biota presence, with contamination confounding microbial classifications.
Single-nucleus sequencing revealed significant myeloid cell heterogeneity in CRPC, with varying degrees of oxidative stress-induced DNA damage I linked to myeloid-derived reactive oxygen species {ROS). This heterogeneity extended to tumour subclones, with genomic instability and replication I stress driving therapeutic sensitivity to ATR inhibition. Notably, the overexpression of the prognostic marker POLQ was associated with replication [ stress and ATR inhibition sensitivity, highlighting a potential therapeutic target for CRPC. These findings provide insights into the complex interplay: between the microbiome, inflammation, and cellular mechanisms driving CRPC progression and resistance and merit further functional validations.
Citation
2025
DOI
Source Title
Publisher
Institute of Cancer Research (University Of London)
ISSN
eISSN
Collections
Research Team
Cancer Biomarkers