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Extensive androgen receptor enhancer heterogeneity in primary prostate cancer patients underlies transcriptional diversity and metastatic potential

ABSTRACT: Extensive androgen receptor enhancer heterogeneity in primary prostate cancer patients underlies transcriptional diversity and metastatic potential

PROVIDER: PRJNA898381 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	SRR22195379_1.fastq.gz	Fastqsanger.gz
	SRR22195379_2.fastq.gz	Fastqsanger.gz
	SRR22195380_1.fastq.gz	Fastqsanger.gz
	SRR22195380_2.fastq.gz	Fastqsanger.gz
	SRR22195381_1.fastq.gz	Fastqsanger.gz

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Extensive androgen receptor enhancer heterogeneity in primary prostate cancer patients underlies transcriptional diversity and metastatic potential

Project description:Androgen receptor (AR) drives prostate cancer (PCa) development and progression. AR chromatin binding profiles are highly plastic and form recurrent programmatic changes that differentiate disease stages, subtypes and patient outcomes. While prior studies focused on concordance between patient subgroups, inter-tumor heterogeneity of AR enhancer selectivity remains unexplored. Here we report high levels of AR chromatin binding heterogeneity in human primary prostate tumors, that unexpectedly strongly overlap with heterogeneity observed in healthy prostate epithelium. Such heterogeneity has functional consequences, as somatic mutations converge on commonly-shared AR sites in primary over metastatic tissues. In contrast, less-frequently shared AR sites associate strongly with AR-driven gene expression, while such heterogeneous AR enhancer usage also distinguishes patients’ outcome. These findings indicate that epigenetic heterogeneity in primary disease is directly informative for risk of biochemical relapse. Cumulatively, our results illustrate an extraordinary level of AR enhancer heterogeneity in primary PCa driving differential expression and clinical impact.

2022-11-12 | GSE217319 | GEO

Extensive androgen receptor enhancer heterogeneity in primary prostate cancers underlies transcriptional diversity and metastatic potential.

Project description:Androgen receptor (AR) drives prostate cancer (PCa) development and progression. AR chromatin binding profiles are highly plastic and form recurrent programmatic changes that differentiate disease stages, subtypes and patient outcomes. While prior studies focused on concordance between patient subgroups, inter-tumor heterogeneity of AR enhancer selectivity remains unexplored. Here we report high levels of AR chromatin binding heterogeneity in human primary prostate tumors, that overlap with heterogeneity observed in healthy prostate epithelium. Such heterogeneity has functional consequences, as somatic mutations converge on commonly-shared AR sites in primary over metastatic tissues. In contrast, less-frequently shared AR sites associate strongly with AR-driven gene expression, while such heterogeneous AR enhancer usage also distinguishes patients' outcome. These findings indicate that epigenetic heterogeneity in primary disease is directly informative for risk of biochemical relapse. Cumulatively, our results illustrate a high level of AR enhancer heterogeneity in primary PCa driving differential expression and clinical impact.

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ANDROGEN DRIVES MELANOMA INVASIVENESS AND METASTATIC SPREAD BY INDUCING TUMORIGENIC FUCOSYLATION: Fucoproteomics

Project description:Melanoma incidence and mortality rates are historically higher for men than women. Although emerging studies have highlighted tumorigenic roles for the male sex hormone androgen and its receptor (AR) in melanoma, cellular and molecular mechanisms underlying these sex-associated discrepancies are poorly defined. Here, we delineate a previously undisclosed mechanism by which androgen-activated AR transcriptionally upregulates fucosyltransferase 4 (FUT4) expression, which drives melanoma invasiveness by interfering with adherens junctions (AJs). Global phosphoproteomic and fucoproteomic profiling, coupled with in vitro and in vivo functional validation, further reveals that AR-induced FUT4 fucosylates L1 cell adhesion molecule (L1CAM), which is required for FUT4-increased metastatic capacity. Tumor microarray and gene expression analyses demonstrate that AR-FUT4-L1CAM-AJs signaling correlates with pathological staging in melanoma patients. By delineating key androgen-triggered signaling that enhances metastatic aggressiveness, our findings help to explain sex-associated clinical outcome disparities and highlight AR/FUT4 and its effectors as potential prognostic biomarkers and therapeutic targets in melanoma.

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ANDROGEN DRIVES MELANOMA INVASIVENESS AND METASTATIC SPREAD BY INDUCING TUMORIGENIC FUCOSYLATION: Phosphoproteomics

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Project description:Tumors are heterogeneous and comprised of cells with varying function and ability to disseminate. Despite significant effort, no universal biological marker currently serves as a metric for metastatic potential of solid tumors. Common to disseminating cells from such tumors, however, is the need to modulate their adhesion as they detach from the tumor and migrate through stroma to intravasate. Adhesion strength is heterogeneous even amongst cancer cells within a given population, and using a parallel plate flow chamber, we separated and sorted these populations into weakly and strongly adherent groups; when cultured under stromal conditions, this adhesion phenotype is stable over multiple days, sorting cycles, and common across all epithelial tumor lines investigated. Subpopulations do not show differences in expression of proteins involved in the focal adhesion complex but do exhibit intrinsic focal adhesion assembly as well as contractile differences that result from differential expression of genes involved in microtubules, cytoskeleton linkages, and motor activity. Collectively, these differences drive migration in both 2D and 3D migration assays for weakly adherent cells; these differences are maintained over days in culture, suggesting that adhesion strength can serve as a stable marker for migration and metastatic potential within a given tumor population. Moreover, these data suggest that the fraction of weakly adherent cells present within a tumor could act as a novel physical marker for metastatic potential.

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Project description:Aim: We examined methylation changes in cell-free DNA (cfDNA) in metastatic castration resistant prostate cancer (mCRPC) during treatment. Patients and Methods: Genome-wide methylation analysis of sequentially collected cfDNA samples derived from mCRPC patients undergoing androgen-targeting therapy was performed. Results: Alterations in methylation states of genes previously implicated in prostate cancer progression were observed, and patients that maintained methylation changes throughout therapy tended to have a longer time to clinical progression (TTP). Importantly, we also report that markers associated with a highly aggressive form of the disease, Neuroendocrine-CRPC, were associated with a faster TTP. Conclusion: Our findings highlight the potential of monitoring the cfDNA methylome during therapy in mCRPC, which may serve as predictive markers of response to androgen-targeting agents.

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