Unravelling the function of PSA variants in prostate cancer

Overview

Overview

Prostate cancer (PCa) is the second-most common cancer in men. Prostate-specific antigen (PSA) encoded by the KLK3 gene is the only FDA-approved PCa biomarker for PCa. As a serine protease, PSA can also regulate multiple functions involved in PCa progression and metastasis and is summarised in our recent publications. Immunotherapies, including PSA-targeting therapies, have shown modest improvement in survival, for only a subset of metastatic PCa patients. Not much is known on the immunoregulatory role of PSA or its variants, suggesting that a better understanding of this protease and the variants' role in PCa immune system is vital, to develop efficient therapeutic modalities.

Aims:

1. Investigate the function of PSA variants utilizing in vivo mice models.
2. Annotate and characterise the differences in the immune response in prostate tumour tissues.
3. Validate the immune response utilising cell line models.

References

1. Srinivasan S, Kryza T, Batra J, Clements J. Remodelling of the tumour microenvironment by the kallikrein-related peptidases. Vol. 22, Nature Reviews Cancer. Nature Research; 2022. p. 223–38.
2. Batra J, Srinivasan S, Kryza T, Bock N, Tse BW, Sokolowski KA, et al. Biochemical activity induced by a germline variation in KLK3 (PSA) associates with cellular function and clinical outcome in prostate cancer. 2023; Available from: https://doi.org/10.21203/rs.3.rs-2650312/v1.
3. Moradi A, Srinivasan S, Clements J, Batra J. Beyond the biomarker role: prostate-specific antigen (PSA) in the prostate cancer microenvironment. Vol. 38, Cancer and Metastasis Reviews. Springer; 2019. p. 333–46.
4. Srinivasan S.,...Batra J. (2019) Prostate Cancer Risk-Associated Single-Nucleotide Polymorphism Affects Prostate-Specific Antigen Glycosylation and Its Function. Clin Chem, 65, e1-e9.
5. Kote-Jarai Z., ...Batra J et al. (2011) Identification of a novel prostate cancer susceptibility variant in the KLK3 gene transcript. Hum Genet, 129, 687-694.

Research activities

This project proposes to combine expertise in in vivo mice models, histology, tumor biology, with multidisciplinary approaches involving single cell RNA sequencing (scRNA-seq), in-vivo imaging, AI-based tissue analysis and expertise in cellular assays to elucidate the role of PSA and its variants in prostate cancer etiology and disease progression.

You will also gain experience in the above-mentioned techniques, including:

• immunohistochemistry
• cellular assays (proliferation, migration) and co-culture assays
• scRNA-seq.

Outcomes

A critical area of unmet need in PCa clinical management is a clear understanding of “who needs treatment, and when do they need it.” This project will span multidisciplinary collaborative team to achieve high-impact research to address this critical knowledge gap in prostate cancer.

The integrated approach will lead to extensive insights in understanding the role of PSA in PCa pathogenesis, which has been an enigma to date and would explain why certain cancers alone progress to high-grade metastatic tumours.

The translational impact of this project may be substantial, as elucidation of the role of PSA and variants' role in the tumour microenvironment will contribute to the identification of novel therapeutic strategies for prostate cancer.

Skills and experience

Experience in mammalian cell culture is beneficial but not necessary. However, student should have an interest to acquire these technical skills. Knowledge of basic biochemistry, cell and molecular biology, and basic laboratory techniques will be an advantage.

Scholarships

You may be eligible to apply for a research scholarship.

Explore our research scholarships

Keywords

• prostate cancer
• biomarker
• immunology
• prostate-specific antigen
• genetic variants

Contact

Contact the supervisor for more information.