Intra-tumoural heterogeneity (ITH) is a known factor in the emergence of drug resistance in cancer. Here, we performed single-cell RNA-sequencing of 12 patient-derived xenograft (PDX) models of advanced and metastatic prostate cancer to gain insights into how transcriptional ITH drives resistance to androgen deprivation therapy (ADT), a commonly used treatment against high-grade prostate cancer. This collection of PDXs includes both therapy-naïve and ADT-resistant models, including several with neuroendocrine differentiation.
Substantial transcriptional ITH was observed both within and between PDX lines, with 3 – 8 distinct sub-populations identified in each line. Almost all PDXs had a stem-like sub-population expressing epithelial-mesenchymal transition (EMT) genes and/or a quiescent sub-population, offering both plasticity and dormancy as possible commonly co-existing treatment resistance mechanisms. Sub-populations expressing genes in pathways that are potentially therapeutically targetable were found in all PDXs but the combination of targetable pathways differed in each PDX.
Upon castration of its host, two distinct new tumour sub-populations simultaneously emerged from a treatment-naïve adenocarcinoma PDX. One sub-population underwent neuroendocrine transdifferentiation into an androgen-independent state while other showed sustained androgen receptor signalling. Both sub-populations contained actively dividing cells but showed divergent expression of key master regulators.
Our findings indicate transcriptional ITH driven by cellular plasticity may provide multiple alternative pathways prostate cancer cells found within the same tumour can use to gain resistance to androgen deprivation and other treatments. Defining and targeting the mechanisms underlying this plasticity will be essential for achieving successful treatment outcomes in advanced and metastatic prostate cancer.