Prostate Pathology of Genetically Engineered Mice: Definitions and Classification. The Consensus Report From the Bar Harbor Meeting of the Mouse Models of Human Cancer Consortium Prostate Pathology Committee

Drug resistance in cancer is often linked to changes in tumor cell state or lineage, but the molecular mechanisms driving this plasticity remain unclear. Using murine organoid and genetically engineered mouse models, we investigated the causes of lineage plasticity in prostate cancer and its relationship to antiandrogen resistance. We found that plasticity initiates in an epithelial population defined by mixed luminal-basal phenotype and that it depends on increased Janus kinase (JAK) and fibroblast growth factor receptor (FGFR) activity. Organoid cultures from patients with castration-resistant disease harboring mixed-lineage cells reproduce the dependency observed in mice by up-regulating luminal gene expression upon JAK and FGFR inhibitor treatment. Single-cell analysis confirms the presence of mixed-lineage cells with increased JAK/STAT (signal transducer and activator of transcription) and FGFR signaling in a subset of patients with metastatic disease, with implications for stratifying patients for clinical trials. Description Understanding prostate cancer plasticity Cellular plasticity is the ability of cells to alter their identity and acquire new biological properties. In the context of cancer, plasticity may explain how certain tumors evolve and become resistant to therapy. Chan et al. investigated the molecular mechanisms underlying lineage plasticity in late-stage prostate cancer. Using a number of model systems, including human organoid cultures, activation of Janus kinase-signal transducer and activator of transcription (JAK/STAT) and fibroblast growth factor receptor (FGFR) signaling was found to drive prostate tumor plasticity. Pharmacological targeting of the JAK and FGFR pathways promoted lineage reprogramming in biopsy samples from castration-resistant prostate cancer patients. These findings provide insights that may help to curb prostate cancer progression and resensitize resistant tumors to effective therapies. —PNK In prostate tumors, expansion of epithelial cells of mixed lineages is dependent on JAK/STAT and fibroblast growth factor receptor activation.

Lineage plasticity in prostate cancer depends on JAK/STAT inflammatory signaling

The prostate is part of the reproductive organs in male mammals. Many of the cells lining the inside of the prostate – known as ‘luminal cells’ – need hormones to survive. Certain treatments for prostate cancer, including surgical and chemical castration, lead to fewer hormones reaching the prostate, which shrinks as luminal cells die. But some of these luminal cells are able to survive the damaging effects of castration, rebuilding the prostate upon treatment with hormones, which can lead to the cancer reappearing. It is unclear which type of luminal cells survive during periods without hormones and are responsible for regenerating the prostate. RUNX1 is a protein responsible for switching genes on and off, and is usually found in blood cells, which it helps to mature and perform their roles, but has also been detected in tissues that depend on hormones. Since the luminal cells of the prostate rely on hormones, could RUNX1 also be present in these cells? To answer this question, Mevel et al. used mice to determine where and when RUNX1 is found in prostate cells. Mevel et al. detected high levels of RUNX1 in a patch of luminal cells at the base of the prostate. Samples of these cells were taken for further testing from developing mouse embryos, healthy adult mice and mice in which the prostate was regenerating after surgical castration. Mevel et al. found that these cells were a distinct subtype of luminal cells that were able to resist the effects of castration – they survived without hormones. Though these cells were present during the early stages of prostate embryonic development and in healthy adult prostate tissue, they were not responsible for rebuilding the prostate after castration. Mevel et al.’s results indicate that, in mice, RUNX1 may act as a marker for a subset of luminal cells that can survive after castration. Further probing the roles of these castration-resistant luminal cells in normal and cancerous prostate tissue may improve the outcome of patients with prostate cancer treated with hormone deprivation therapy.

RUNX1 marks a luminal castration resistant lineage established at the onset of prostate development

Understanding and targeting prostate cancer cell heterogeneity and plasticity

Understanding and targeting prostate cancer cell heterogeneity and plasticity.

Understanding the cellular constituents of the prostate is essential for identifying the cell of origin for prostate adenocarcinoma. Here, we describe a comprehensive single-cell atlas of the adult mouse prostate epithelium, which displays extensive heterogeneity. We observe distal lobe-specific luminal epithelial populations (LumA, LumD, LumL, and LumV), a proximally enriched luminal population (LumP) that is not lobe-specific, and a periurethral population (PrU) that shares both basal and luminal features. Functional analyses suggest that LumP and PrU cells have multipotent progenitor activity in organoid formation and tissue reconstitution assays. Furthermore, we show that mouse distal and proximal luminal cells are most similar to human acinar and ductal populations, that a PrU-like population is conserved between species, and that the mouse lateral prostate is most similar to the human peripheral zone. Our findings elucidate new prostate epithelial progenitors, and help resolve long-standing questions about anatomical relationships between the mouse and human prostate.

A single-cell atlas of the mouse and human prostate reveals heterogeneity and conservation of epithelial progenitors

Author response: A single-cell atlas of the mouse and human prostate reveals heterogeneity and conservation of epithelial progenitors

Prostate cancer cell heterogeneity and plasticity: Insights from studies of genetically-engineered mouse models.

Understanding the cellular constituents of the prostate is essential for identifying the cell of origin for benign prostatic hyperplasia and prostate adenocarcinoma. Here we describe a comprehensive single-cell atlas of the adult mouse prostate epithelium, which demonstrates extensive heterogeneity. We observe distinct lobe-specific luminal epithelial populations (LumA, LumD, LumL, and LumV) in the distal region of the four prostate lobes, a proximally-enriched luminal population (LumP) that is not lobe-specific, as well as a periurethral population (PrU) that shares both basal and luminal features. Functional analyses suggest that LumP and PrU cells have multipotent progenitor activity in organoid formation and tissue reconstitution assays. Furthermore, we show that mouse distal and proximal luminal cells are most similar to human acinar and ductal populations, that a PrU-like population is conserved between species, and that the mouse lateral prostate is most similar to the human peripheral zone. Our findings elucidate new prostate epithelial progenitors, and help resolve long-standing questions about the anatomical relationships between the mouse and human prostate.

https://www.biorxiv.org/content/biorxiv/early/2020/05/31/2020.05.29.123836.full.pdf

Weiping Li

Papers

A single-cell atlas of the mouse and human prostate reveals heterogeneity and conservation of epithelial progenitors

Author response: A single-cell atlas of the mouse and human prostate reveals heterogeneity and conservation of epithelial progenitors

Prostate cancer cell heterogeneity and plasticity: Insights from studies of genetically-engineered mouse models.

A single-cell atlas of the mouse and human prostate reveals heterogeneity and conservation of epithelial progenitors