Establishment of a Multidimensional Screening Platform for the Functionalisation of Putative Drivers of Castration Resistant Prostate Cancer
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Embargo End Date
2026-07-12
ICR Authors
Authors
Hind, L
Document Type
Thesis or Dissertation
Date
2026-01-12
Date Accepted
Abstract
Advanced prostate cancer is a complex disease with significant heterogeneity, characterised by intricate interactions with the tumour
microenvironment and limited responsiveness to standard immunotherapies. This thesis focuses on developing a multimodal
platform to functionally characterise a class of transcriptional regulators that undergo genetic alterations in advanced disease. While
individually rare in primary tumours, these aberrations are significantly more frequent as a group in later stages, suggesting a crucial
role in cancer progression, castration resistance, and metastasis. Despite their clinical importance, their precise function remains
largely unknown.
These genetic alterations are thought to drive disease progression through various mechanisms, including phenotypic plasticity,
transcriptional heterogeneity, phenotypic inertia, and microenvironmental modulation. However, it remains unclear which of these
aberrations are key drivers, whether they act independently or collectively, and whether their effects are direct or mediated through
secondary pathways. Addressing these uncertainties requires a robust multimodal platform capable of integrating phenotypic and
molecular data across in vitro and in vivo models to capture their full impact on tumour biology.
This thesis begins by examining the genetic landscape and clinical outcomes of advanced castration-resistant prostate cancer
(CRPC) before narrowing its focus to a specific class of transcriptional regulators implicated in disease progression. The central
objective is to establish and validate a CRISPR-based screening system that enables systematic functional analysis of these
aberrations. This platform utilises guide RNA (gRNA) linked to a protein barcode (pro-code), enabling precise, multi-platform tracking
of genetic perturbations.
The methodology involves a thorough literature review to identify key genes, the design and optimisation of CRISPR gRNA libraries,
refinement of cloning and library balancing procedures, and the development of antibody panels for CyTOF and Phenocycler
technologies. The platform’s effectiveness is demonstrated through large-scale functional screens integrating genetic and phenotypic
data. Ultimately, this work establishes a platform designed to enhance our understanding of disease progression, supporting the
development of more precise and effective therapeutic strategies.
Citation
2026
DOI
Source Title
Publisher
Institute of Cancer Research (University Of London)
ISSN
eISSN
Collections
Research Team
Tumour Func Heterogeneity