Transcriptional mediators of treatment resistance in lethal prostate cancer

Abstract

Metastatic castration resistant prostate cancer (mCRPC) is primarily treated with therapies that prevent transcriptional activity of the androgen receptor (AR), cause DNA damage, or prevent cell division. Clinical resistance to these therapies, including second-generation androgen-targeting compounds such as enzalutamide and abiraterone, is nearly universal. Other treatment modalities, including immune checkpoint inhibitors, have provided minimal benefit except in rare subsets of patients1,2. Both tumour intrinsic and extrinsic cellular programs contributing to therapeutic resistance remain areas of active investigation. Here we use full-length single-cell RNA-sequencing (scRNA-seq) to identify the transcriptional states of cancer and immune cells in the mCRPC microenvironment. Within cancer cells, we identified transcriptional patterns that mediate a significant proportion of inherited risk for prostate cancer, extensive heterogeneity in AR splicing within and between tumours, and vastly divergent regulatory programs between adenocarcinoma and small cell carcinoma. Moreover, upregulation of TGF-β signalling and epithelial-mesenchymal transition (EMT) were both associated with resistance to enzalutamide. We found that some lymph node metastases, but no bone metastases, were heavily infiltrated by dysfunctional CD8+ T cells, including cells undergoing dramatic clonal expansion during enzalutamide treatment. Our findings suggest avenues for rational therapeutic approaches targeting both tumour-intrinsic and immunological pathways to combat resistance to current treatment options.

Tumor and immune reprogramming during immunotherapy in advanced renal cell carcinoma

“…Where available, additional tissue was used for whole exome sequencing (samples P55, P915, P913, P906, P76) or panel sequencing via OncoPanel (sample P90), with downstream bioinformatic analyses as previously described ( He et al., 2021 ). Briefly, exome capture was performed using Illumina’s Rapid Capture Exome Kit, reads were aligned using BWA v0.5.9 ( Li and Durbin, 2009 ), somatic mutation calling was performed using MuTect ( Cibulskis et al., 2013 ), and copy number alterations were called using FACETS ( Shen and Seshan, 2016 ).…”

Intra-epithelial non-canonical Activin A signalling safeguards prostate progenitor quiescence

“…Moreover, MAP3K7 loss has been linked to genomic instability in human prostate cancer cell lines 56 and found to promote an aggressive transcriptional programme in prostate tumours, based on a recent systematic pan-cancer analysis 57 . In contrast, genetic alterations rarely affect TGFB1 receptors ( e.g ., TGFBR2 ) or SMAD factors ( e.g., SMAD4 ), and enhanced canonical TGF-β signalling has been reported in metastatic biopsies in therapy-resistant prostate cancer patients 58 . We speculate that loss of the non-canonical TGF-β arm could impair the cytostatic response, while sparing the well-known transforming potential of the TGF-β canonical pathway.…”

Human prostate cancer bone metastases have an actionable immunosuppressive microenvironment

“…Interestingly, TGFB1 has been recently shown to be a molecular mediator for T helper cell polarization toward Th17 in response to immune checkpoint therapy in the bone metastatic microenvironment and blocking it in combination with the immune checkpoint inhibitors improved survival in a mouse model of prostate cancer (Jiao et al, 2019). Further, a recent study by an independent group suggest that exposure to the anti-androgen drug enzaluatamide is associated with an increased tumor-intrinsic activation of TGFβ signaling and EMT signature in metastatic castration resistant prostate cancer (He, 2020), suggesting that resistance to anti-androgen treatment may be induced by TGFB1. In contrast to the TAM immunosuppressive M2-like signature, TIM cells had a pro-inflammatory monocyte signature with high expression of pro-inflammatory cytokines such as IL1-B and TNF ( Fig.…”