Profiling of epithelial functional states and fibroblast phenotypes in hormone therapy-naive localised prostate cancer

Apostolov, E.; Roden, D. L.; Holliday, H.; Cazet, A.; Harvey, K.; Zhang, H.; Wu, S. Z.; van der Leij, S.; Selth, L. A.; Bartonicek, N.; Al-Eryani, G.; He, M.; Lundeberg, J.; Reeves, J.; Kench, J. G.; Potter, A. J.; Stricker, P. D.; Joshua, A. M.; Horvath, L. G.; Swarbrick, A.

doi:10.1101/2024.10.23.619925

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bioRxiv · 10.1101/2024.10.23.619925

Profiling of epithelial functional states and fibroblast phenotypes in hormone therapy-naive localised prostate cancer

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Abstract

Localised prostate cancers (PCa) are heterogeneous and multifocal, with diverse outcomes. Current prognostic methods are epithelium-centric, overlooking the complex cellular landscape within the tumour microenvironment (TME), which remains incompletely characterised. We performed a comprehensive analysis of cancerous and adjacent-benign cores from 24 patients with hormone therapy-naive localised PCa using single-cell RNA-sequencing. By integrating copy number variation and transcriptional signatures, we classified epithelial cells across a malignant spectrum, revealing widespread molecular perturbation. We found an expansion of Club cell phenotypes, suggestive of Luminal dedifferentiation. We also performed a detailed annotation of stromal phenotypes, focusing on fibroblasts, and identified a novel peri-neural fibroblast population. Spatial transcriptomics elucidated the precise anatomical distribution of CAFs within the PCa TME. This study provides a valuable foundation for advancing our understanding of PCa pathobiology and developing a comprehensive cellular model of the disease. Statement of SignificanceOur study leverages single-cell RNA-sequencing and spatial transcriptomics to provide a comprehensive cellular annotation of hormone therapy-naive localised PCa. We reveal widespread molecular perturbations in epithelial cells and map distinct fibroblast populations to specific anatomical niches. Notably, we identify a novel peri-neural phenotype associated with nerves, which merits further functional characterisation and exploration as a potential therapeutic target.

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Apostolov, E., Roden, D. L., Holliday, H., Cazet, A., Harvey, K., Zhang, H., Wu, S. Z., van der Leij, S., Selth, L. A., Bartonicek, N., Al-Eryani, G., He, M., Lundeberg, J., Reeves, J., Kench, J. G., Potter, A. J., Stricker, P. D., Joshua, A. M., Horvath, L. G., Swarbrick, A.. 2024-10-28. Profiling of epithelial functional states and fibroblast phenotypes in hormone therapy-naive localised prostate cancer. https://doi.org/10.1101/2024.10.23.619925

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