Integration Analysis of Single‐Cell Multi‐Omics Reveals Prostate Cancer Heterogeneity

Advanced Science, Journal Year: 2024, Volume and Issue: 11(18)

Published: March 14, 2024

Abstract Prostate cancer (PCa) is an extensive heterogeneous disease with a complex cellular ecosystem in the tumor microenvironment (TME). However, manner which heterogeneity shaped by tumors and stromal cells, or vice versa, remains poorly understood. In this study, single‐cell RNA sequencing, spatial transcriptomics, bulk ATAC‐sequence are integrated from series of patients PCa healthy controls. A stemness subset club cells marked SOX9 high AR low expression identified, markedly enriched after neoadjuvant androgen‐deprivation therapy (ADT). Furthermore, CD8 + CXCR6 T that function as effector reduced malignant PCa. For transcriptome analysis, machine learning computational intelligence comprehensively utilized to identify diversity prostate cell‐cell communication situ. Macrophage neutrophil state transitions along trajectory progression also examined. Finally, immunosuppressive advanced found be associated infiltration regulatory (Tregs), potentially induced FAP fibroblast subset. summary, delineated stage‐specific at resolution, uncovering their reciprocal crosstalk progression, can helpful promoting diagnosis therapy.

Language: Английский

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The Genomic and Epigenomic Landscape of Double-Negative Metastatic Prostate Cancer

Cancer Research, Journal Year: 2023, Volume and Issue: 83(16), P. 2763 - 2774

Published: June 8, 2023

Abstract Systemic targeted therapy in prostate cancer is primarily focused on ablating androgen signaling. Androgen deprivation and second-generation receptor (AR)–targeted selectively favor the development of treatment-resistant subtypes metastatic castration-resistant (mCRPC), defined by AR neuroendocrine (NE) markers. Molecular drivers double-negative (AR−/NE−) mCRPC are poorly defined. In this study, we comprehensively characterized treatment-emergent integrating matched RNA sequencing, whole-genome bisulfite sequencing from 210 tumors. AR−/NE− tumors were clinically molecularly distinct other subtypes, with shortest survival, amplification chromatin remodeler CHD7, PTEN loss. Methylation changes CHD7 candidate enhancers linked to elevated expression AR−/NE+ Genome-wide methylation analysis nominated Krüppel-like factor 5 (KLF5) as a driver phenotype, KLF5 activity was RB1 These observations reveal aggressiveness could facilitate identification therapeutic targets highly aggressive disease. Significance: Comprehensive characterization five identified transcription factors that drive each subtype showed has worst prognosis.

Language: Английский

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Circulating tumor extracellular vesicles to monitor metastatic prostate cancer genomics and transcriptomic evolution

Cancer Cell, Journal Year: 2024, Volume and Issue: 42(7), P. 1301 - 1312.e7

Published: July 1, 2024

Extracellular vesicles (EVs) secreted by tumors are abundant in plasma, but their potential for interrogating the molecular features of through multi-omic profiling remains widely unexplored. Genomic and transcriptomic circulating EV-DNA EV-RNA isolated from vitro vivo models metastatic prostate cancer (mPC) reveal a high contribution tumor material to EV-loaded DNA/RNA, validating findings two cohorts longitudinal plasma samples collected patients during androgen receptor signaling inhibitor (ARSI) or taxane-based therapy. genomic recapitulate matched-patient biopsies DNA (ctDNA) associate with clinical progression. We develop novel approach enable (RExCuE). report how transcriptome EVs is enriched tumor-associated transcripts, captures certain patient features, reflects on-therapy adaptation changes. Altogether, we show that EV enables mPC liquid biopsy.

Language: Английский

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ONECUT2 acts as a lineage plasticity driver in adenocarcinoma as well as neuroendocrine variants of prostate cancer

Nucleic Acids Research, Journal Year: 2024, Volume and Issue: 52(13), P. 7740 - 7760

Published: June 27, 2024

Abstract Androgen receptor- (AR-) indifference is a mechanism of resistance to hormonal therapy in prostate cancer (PC). Here we demonstrate that ONECUT2 (OC2) activates through multiple drivers associated with adenocarcinoma, stem-like and neuroendocrine (NE) variants. Direct OC2 gene targets include the glucocorticoid receptor (GR; NR3C1) NE splicing factor SRRM4, which are key lineage plasticity. Thus, OC2, despite its previously described NEPC driver function, can indirectly activate portion AR cistrome epigenetic activation GR. Mechanisms by regulates expression promoter binding, enhancement genome-wide chromatin accessibility, super-enhancer reprogramming. Pharmacologic inhibition suppresses plasticity reprogramming induced signaling inhibitor enzalutamide. These results promotes range drug mechanisms treatment-emergent variation PC support enhanced efforts therapeutically target as means suppressing treatment-resistant disease.

Language: Английский

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An Atlas of Accessible Chromatin in Advanced Prostate Cancer Reveals the Epigenetic Evolution during Tumor Progression

Cancer Research, Journal Year: 2024, Volume and Issue: 84(18), P. 3086 - 3100

Published: July 11, 2024

Metastatic castration-resistant prostate cancer (mCRPC) is a lethal disease that resists therapy targeting androgen signaling, the primary driver of cancer. mCRPC receptor (AR) inhibitors by amplifying AR signaling or evolving into therapy-resistant subtypes do not depend on AR. Elucidation epigenetic underpinnings these could provide important insights drivers resistance. In this study, we produced chromatin accessibility maps linked to binding lineage-specific transcription factors (TF) performing assay for transposase-accessible sequencing 70 tissue biopsies integrated with transcriptome and whole-genome sequencing. had distinct global profile function. Analysis TF occupancy across accessible revealed 203 TFs associated subtypes. Notably, ZNF263 was identified as putative significant impact gene activity in double-negative subtype (AR- neuroendocrine-), potentially activating MYC targets. Overall, analysis provides valuable changes occur during progression mCRPC. Significance: Integration large cohort transcriptome, whole-genome, ATAC characterizes advanced identifies subtype-specific modulate oncogenic programs.

Language: Английский

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Identification of an anaplastic subtype of prostate cancer amenable to therapies targeting SP1 or translation elongation

Science Advances, Journal Year: 2024, Volume and Issue: 10(14)

Published: April 3, 2024

Histopathological heterogeneity is a hallmark of prostate cancer (PCa). Using spatial and parallel single-nucleus transcriptomics, we report an androgen receptor (AR)-positive but neuroendocrine-null primary PCa subtype with morphologic molecular characteristics small cell carcinoma. Such cell-like (SCLPC) clinically aggressive low AR, high stemness proliferation, activity. Molecular characterization prioritizes protein translation, represented by up-regulation many ribosomal genes, SP1, transcriptional factor that drives SCLPC phenotype overexpresses in castration-resistant (CRPC), as two potential therapeutic targets AR-indifferent CRPC. An SP1-specific inhibitor, plicamycin, effectively suppresses CRPC growth vivo. Homoharringtonine, Food And Drug Administration-approved translation elongation impedes progression preclinical models patients We construct SCLPC-specific signature capable stratifying for drug selectivity. Our studies reveal the existence admixed pathology, which may mediate tumor relapse, establish SP1 actionable

Language: Английский

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LSD1 promotes prostate cancer reprogramming by repressing TP53 signaling independently of its demethylase function

JCI Insight, Journal Year: 2023, Volume and Issue: 8(15)

Published: July 13, 2023

Lysine-specific demethylase 1 (LSD1) is a histone that promotes stemness and cell survival in cancers such as prostate cancer. Most malignancies are adenocarcinomas with luminal differentiation. However, some tumors undergo cellular reprogramming to more lethal subset termed neuroendocrine cancer (NEPC) neuronal The frequency of NEPC increasing since the widespread use potent androgen receptor signaling inhibitors. Currently, there no effective treatments for NEPC. We previously determined LSD1 adenocarcinoma tumors. role unknown. Here, we highly upregulated versus patient suppression RNAi or allosteric inhibitors - but not catalytic reduced survival. RNA-Seq analysis revealed represses pathways linked differentiation, TP53 was top reactivated pathway. confirmed suppressed pathway by reducing occupancy at target genes while LSD1's function dispensable this effect. Mechanistically, inhibition disrupted LSD1-HDAC interactions, acetylation targets. Finally, tumor growth vivo. These findings suggest blocking noncatalytic may be promising treatment strategy

Language: Английский

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Genomic Profiling of Metastatic Castration-Resistant Prostate Cancer Samples Resistant to Androgen Receptor Pathway Inhibitors

Clinical Cancer Research, Journal Year: 2023, Volume and Issue: 29(21), P. 4504 - 4517

Published: June 26, 2023

The androgen receptor axis inhibitors (ARPI; e.g., enzalutamide, abiraterone acetate) are administered in daily practice for men with metastatic castration-resistant prostate cancer (mCRPC). However, not all patients respond, and mechanisms of both primary acquired resistance remain largely unknown.In the prospective trial MATCH-R (NCT02517892), 59 mCRPC underwent whole-exome sequencing (WES) and/or RNA (RNA-seq) samples collected before starting ARPI. Also, 18 biopsy at time resistance. objectives were to identify genomic alterations associated ARPIs as well describe clonal evolution. Associations transcriptomic determined using Wilcoxon Fisher exact tests.WES analysis indicated that no single-gene strongly RNA-seq showed (AR) gene expression levels similar between responders nonresponders. RNA-based pathway found had a higher Hedgehog score, lower AR score NOTCH than response. Subclonal evolution acquisition new AR-related genes or neuroendocrine differentiation do induce significant changes tumor transcriptome most patients; however, programs cell proliferation enriched resistant samples.Low activity, activation stemness programs, ARPIs' resistance, whereas was subclonal evolution, events, differentiation. See related commentary by Slovin, p. 4323.

Language: Английский

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Preclinical Models of Neuroendocrine Prostate Cancer

Current Protocols, Journal Year: 2023, Volume and Issue: 3(5)

Published: May 1, 2023

Abstract Prostate cancer (PCa) is the most common malignancy and second leading cause of cancer‐related death amongst men in United States. Neuroendocrine prostate (NEPC) can either arise de novo or emerge as a consequence therapy. De NEPC rare, with an incidence <2% all PCa cases. In contrast, treatment‐induced frequent >20% patients metastatic castration‐resistant (CRPC) reported to progress neuroendocrine (NE) differentiation. The emergence linked increased therapeutic pressure, due broad application androgen deprivation therapy (ADT) for management development novel more potent receptor (AR) pathway inhibitors. high‐grade tumor type characterized by aggressive phenotype clinical behavior. Patients affected frequently develop visceral metastases have poor prognosis. molecular mechanisms underlying progression are still poorly understood. Transcriptional epigenetic reprogramming appears be involved NE progression. this review, we aim provide comprehensive view available models detailing their strengths limitations. Moreover, describe approaches expand repertoire preclinical better study, prevent, reverse NEPC. integration multiple along omics will important insights understand disease devise strategies near future. © 2023 Authors. Current Protocols published Wiley Periodicals LLC. Basic Protocol 1 : Generation organoids starting from gland GEMM human PDX 2 Ex vivo sphere formation

Language: Английский

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Epigenomics‐guided precision oncology: Chromatin variants in prostate tumor evolution

International Journal of Cancer, Journal Year: 2025, Volume and Issue: unknown

Published: Jan. 23, 2025

Abstract Prostate cancer is a common malignancy that in 5%–30% leads to treatment‐resistant and highly aggressive disease. Metastasis‐potential treatment‐resistance thought rely on increased plasticity of the cells—a mechanism whereby cells alter their identity adapt changing environments or therapeutic pressures create cellular heterogeneity. To understand molecular basis this plasticity, genomic studies have uncovered genetic variants capture clonal heterogeneity primary tumors metastases. As largely driven by non‐genetic events, complementary epigenomics are now being conducted identify chromatin . These variants, defined as loci show changes state due loss gain epigenomic marks, inclusive histone post‐translational modifications, DNA methylation considered fundamental units In prostate hold promise guiding new era precision oncology. review, we explore role cancer, focusing how contribute tumor evolution therapy resistance. We therefore discuss impact stochastic highlighting value single‐cell sequencing liquid biopsy assays uncover targets biomarkers. Ultimately, review aims support oncology, utilizing insights from improve patient outcomes.

Language: Английский

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