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Integrated single-cell analysis defines the epigenetic basis of castration-resistant prostate luminal cells (scRNA-seq)

ABSTRACT: Understanding prostate response to castration and androgen receptor signaling inhibitors (ARSI) is critical to improving long-term prostate cancer (PCa) patient survival. Here we use a multi-omics approach on 229,794 single cells to create a mouse single-cell reference atlas better suited to interpreting mouse prostate biology and castration response. Our reference atlas refines single-cell annotations and provides chromatin context, which, when coupled with mouse lineage tracing demonstrates that the castration-resistant luminal cells are distinct from the pre-existent urethra-proximal stem/progenitor cells. Molecular pathway analysis and therapeutic studies further implicate JUN/FOS, WNT/b-Catenin, FOXQ1, NFkB, and JAK/STAT pathways as the major drivers of castration-resistant luminal populations with high relevance to human PCa. Importantly, we demonstrate the utility of our datasets, which can be explored through an interactive portal (https://visportal.roswellpark.org/data/tang/), to aid in developing novel combination treatments with ARSI for advanced PCa patients.

ORGANISM(S): Mus musculus

PROVIDER: GSE227108 | GEO | 2024/06/14

REPOSITORIES: GEO

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Integrated single-cell analysis defines the epigenetic basis of castration-resistant prostate luminal cells (scATAC-seq)

Project description:Understanding prostate response to castration and androgen receptor signaling inhibitors (ARSI) is critical to improving long-term prostate cancer (PCa) patient survival. Here we use a multi-omics approach on 229,794 single cells to create a mouse single-cell reference atlas better suited to interpreting mouse prostate biology and castration response. Our reference atlas refines single-cell annotations and provides chromatin context, which, when coupled with mouse lineage tracing demonstrates that the castration-resistant luminal cells are distinct from the pre-existent urethra-proximal stem/progenitor cells. Molecular pathway analysis and therapeutic studies further implicate JUN/FOS, WNT/b-Catenin, FOXQ1, NFkB, and JAK/STAT pathways as the major drivers of castration-resistant luminal populations with high relevance to human PCa. Importantly, we demonstrate the utility of our datasets, which can be explored through an interactive portal (https://visportal.roswellpark.org/data/tang/), to aid in developing novel combination treatments with ARSI for advanced PCa patients.

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Project description:Prostate cancer (PCa) is heterogeneous containing both phenotypically differentiated and undifferentiated tumor cells. An important unanswered question is whether these two populations of PCa cells are functionally different. Here we report the distinct molecular, cellular, and tumor-propagating properties of PCa cells that express high (i.e., PSA+) and low (PSA-/lo) levels of the differentiation marker PSA (prostatespecific antigen). PSA-/lo PCa cells are quiescent and resistant to multiple stresses including androgen deprivation, exhibit high clonogenic potential, and possess long-term tumor-propagating capacity in male mice. They preferentially express stem cell-associated genes and can undergo asymmetric cell division generating PSA+ cells. Importantly, PSA-/lo PCa cells can initiate robust tumor development in castrated hosts, survive androgen deprivation, and harbor highly tumorigenic castration-resistant PCa cells that can be further enriched using the ALDH+CD44+α2β1+ phenotype. In contrast, PSA+ PCa cells possess more limited tumor-propagating capacity, mainly undergo symmetric division, and are sensitive to castration. Together, our study suggests that PSA-/lo and PSA+ PCa cells are functionally distinct and PSA-/lo cells may represent one critical source of castration-resistant PCa cells. There are two sets of samples in this study corresponding to two different prostate cancer cell lines LNCaP and LAPC9. Both LNCaP and LAPC9 sets include 3 technical triplicates each that were performed onvdual color arrays and each individual array includes comparison between PSA- (Cy5) and PSA+ (Cy3) cells of the respective cell line.

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Project description:Despite the clinical benefit of androgen-deprivation therapy (ADT), the majority of patients with advanced prostate cancer (PCa) ultimately develop lethal castration-resistant prostate cancer (CRPC). In this study, we identified thioesterase superfamily member 6 (THEM6) as a marker of ADT resistance in PCa. In patients, THEM6 expression correlates with progressive disease and is associated with poor survival. THEM6 deletion reduces in vivo tumour growth and restores castration sensitivity in orthograft models of CRPC. Mechanistically, THEM6 is located at the endoplasmic reticulum (ER) membrane and controls lipid homeostasis by regulating intracellular levels of ether lipids. As a consequence, THEM6 loss in CRPC cells significantly alters ER function, preventing lipid-mediated induction of ATF4 and reducing de novo sterol biosynthesis. Finally, we show that THEM6 is required for the establishment of the MYC-induced stress response. Thus, similar to PCa, THEM6 loss significantly impairs tumorigenesis in the MYC-dependent subtype of triple negative breast cancer. Altogether our results highlight THEM6 as a novel component of the treatment-induced stress response and a promising target for the treatment of CRPC and MYC-driven cancer.

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