Deng, Daqi; (2025) Integrative analyses with organoid modelling reveal the biology of kidney cancer. Doctoral thesis (Ph.D), UCL (University College London).

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Abstract

The genetic evolution of clear cell renal cell carcinoma (ccRCC) has been extensively characterised through observational studies; however, the corresponding molecular and cellular phenotypic adaptations along distinct evolutionary trajectories remain incompletely understood. This gap is largely due to the lack of representative experimental models and limited functional interrogation. In this thesis, I investigate the biology of ccRCC using patient-derived models and propose a conceptual framework outlining key molecular and cellular transitions across tumour initiation, progression, and metastasis. To study initiation, I characterised the basal state of transformation-prone proximal tubular cells and identified a rare subpopulation harbouring chromosome 3p loss. I further evaluated the role of kidney injury in promoting tumour initiation, proposing a model in which injury expands a cell state permissive to transformation. Using patient-derived normal kidney organoids and CRISPR/Cas9 genome editing, I demonstrated that early tumour-initiating alterations, including 3p and VHL loss, do not confer immediate proliferative fitness advantages in vitro. In the context of progression, I established a patient-derived organoid (PDO) biobank for ccRCC and characterised their genomic and transcriptomic landscape. Leveraging integrative analyses incorporating preclinical models and clinical datasets at bulk and single-cell levels, I delineated divergent genotype-to-phenotype relationships focusing on PBRM1- and BAP1-driven trajectories. Functional perturbation of these genes in both tumour and normal organoids confirmed key phenotypic differences related to proliferation, extracellular matrix remodelling, renal lineage commitment, inflammatory signalling, and chromosomal instability. Finally, I demonstrated that CDKN2A is a target of 9p loss and frequently undergoes biallelic inactivation in metastatic ccRCC. Functional perturbation in organoid models revealed context-dependent effects, with CDKN2A-null tumour organoids exhibiting increased proliferation and growth factor independence.

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