An integrated functional and clinical genomics approach reveals genes driving aggressive metastatic prostate cancer
Open accessAbstract
Genomic sequencing of thousands of tumors has revealed many genes associated with specific types of cancer. Similarly, large scale CRISPR functional genomics efforts have mapped genes required for cancer cell proliferation or survival in hundreds of cell lines. Despite this, for specific disease subtypes, such as metastatic prostate cancer, there are likely a number of undiscovered tumor specific driver genes that may represent potential drug targets. To identify such genetic dependencies, we performed genome-scale CRISPRi screens in metastatic prostate cancer models. We then created a pipeline in which we integrated pan-cancer functional genomics data with our metastatic prostate cancer functional and clinical genomics data to identify genes that can drive aggressive prostate cancer phenotypes. Our integrative analysis of these data reveals known prostate cancer specific driver genes, such as AR and HOXB13, as well as a number of top hits that are poorly characterized. In this study we highlight the strength of an integrated clinical and functional genomics pipeline and focus on two top hit genes, KIF4A and WDR62. We demonstrate that both KIF4A and WDR62 drive aggressive prostate cancer phenotypes in vitro and in vivo in multiple models, irrespective of AR-status, and are also associated with poor patient outcome.
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Doxycycline-inducible LNCaPi cells were established previously.
“Doxycycline-inducible LNCaPi cells established previously99 were lentiviral transfected with constructs encoding sgPTGES3 or sgCTRL and puromycin selected.”
From Genome-scale CRISPR screens identify PTGES3 as a direct modulator of androgen receptor function in advanced prostate cancer (2025) · cites this paper as [99]
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- Authors
- Das, R., Sjöström, M., Shrestha, R., Yogodzinski, C., Egusa, E. A., Chesner, L. N., Chen, W. S., Chou, J., Dang, D. K., Swinderman, J. T., Ge, A., Hua, J. T., Kabir, S., Quigley, D. A., Small, E. J., Ashworth, A., Feng, F. Y., & Gilbert, L. A.
- Affiliations
- University of California, San Francisco (US)
- Corresponding author
- Feng, Felix Y.
- Gilbert, Luke A.
- ORCID
- Venue
- Nature Communications
- Published
- 2021-07-29
- Volume
- 12
- Issue
- 1
- Pages
- 4601-4601
- ISSN
- 2041-1723 (ISSN-L)
- PMC
- PMC8322386
- OpenAlex
- W3183624135
- Cited by
- 38
- References
- 69
- Citations by year
- 2026: 2 · 2025: 8 · 2024: 9 · 2023: 6 · 2022: 11 · 2021: 2
- FWCI
- 4.54
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Locations
- Nature Communications (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- RePEc: Research Papers in Economics (submittedVersion)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
- eScholarship (California Digital Library) (submittedVersion, cc-by)
- Funders
- U.S. Department of Defense (W81XWH, W81XWH-20, K99/R00)
- Prostate Cancer Foundation
- National Cancer Institute (K99CA204602, DP2CA239597, R01CA227025, R01CA230516, R00CA204602)
- Topics
- Health Sciences › Medicine › Pulmonary and Respiratory Medicine › Prostate Cancer Treatment and Research
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Chromatin Remodeling and Cancer
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Cancer Genomics and Diagnostics
- Keywords
- metastatic prostate cancer, driver genes, CRISPRi screen, clinical genomics, KIF4A, WDR62, androgen receptor, HOXB13, therapeutic target, tumor aggressiveness, patient outcomes
- MeSH terms
- Animals, Cell Cycle, Cell Movement, Cells, Cultured, Humans, Male, Neoplasm Metastasis, Neoplasm Staging, Nerve Tissue Proteins, Prostatic Neoplasms, Gene Expression Regulation, Neoplastic, Survival Rate, Mice, SCID, Kinesins, Mice, Inbred NOD, Cell Cycle Proteins, Databases, Genetic, Mice, CRISPR-Cas Systems, Heterografts
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Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
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