Metastatic castration-resistant prostate cancer (mCRPC) is known as the lethal and clinically challenging form of prostate carcinogenesis due to its display of extensive cellular and molecular heterogeneity. Patients that exhibit mCRPC pathogenesis experience progressive levels of resistance to many forms of mainstay treatments, such as chemotherapy, surgical procedures and hormone-targeting inhibitors of the androgen-receptor (AR) pathway. Despite the establishment of stratified clinical subtypes for prostate cancer as a whole, these do not provide future insight into a patient’s therapeutic response or the potential development of mCRPC. Immunotherapies have become a breakthrough treatment avenue for a variety cancer types (such as breast, liver and lung cancer) to restore an anti-tumour response through the use of immune checkpoint inhibitors, such as anti-PD-1/L1 and anti-PARP. However, mCRPC patients also continues to show minimal response to immunotherapies due to the unique cellular composition within varying tissue niches that cancer cells migrate to (e.g. bone, lymph node). Additionally, there is a significant lack of knowledge of the driving cellular phenotypes involved in mCRPC carcinogenesis and a link to prognosis and response.
Currently, the confronting challenge of mCRPC is delineating this inherent aggressiveness and resistance present by obtaining and processing lesions from a wide variety of patients and residing tissue microenvironments. In our study, we have collaborated with the Patnaik Lab at the University of Chicago to obtain a unique cohort of ~11,000 cells from six mCRPC patient tumour samples from lymph node and liver tissues for single-cell transcriptomic analysis. Additionally, this collaboration allows us to look into the response of these patients to pre- and post-treatment (4 weeks) of combined immunotherapies of a PD-1 blockade and a PARP inhibitor.
The understanding of mCRPC at this resolution can initiate the investigation of the major cell compartments that play a role in mCRPC, its’ resistance to mainstay treatments and immunotherapies, as well as showcase the heterogeneity of known/novel cell types. Specifically, our work is focused on looking at the epithelial and T-cell mCRPC cellular compartments in more depth. We have found that the epithelial compartment of this mCRPC cohort show distinct patient-specific clusters to exhibit the inter-patient heterogeneity of the malignant cells involved. Single-cell transcriptomics also highlights the expression of key molecular drivers, such as AR, which is seen to have differential expression amongst the patient-specific malignant populations. Our findings show the start of the required investigation of mCRPC through the single-cell perspective.