Simultaneous subset tracing and miRNA profiling of tumor-derived exosomes via dual-surface-protein orthogonal barcoding

Science Advances, Год журнала: 2023, Номер 9(40)

Опубликована: Окт. 4, 2023

The clinical potential of miRNA-based liquid biopsy has been largely limited by the heterogeneous sources in plasma and tedious assay processes. Here, we develop a precise robust one-pot called dual-surface-protein-guided orthogonal recognition tumor-derived exosomes situ profiling microRNAs (SORTER) to detect exosomal miRNAs enhance diagnostic accuracy prostate cancer (PCa). SORTER uses two allosteric aptamers against marker CD63 tumor EpCAM create an labeling barcode achieve selective sorting tumor-specific exosome subtypes. Furthermore, labeled on initiated targeted membrane fusion with liposome probes import miRNA detection reagents, enabling sensitive miRNAs. With signature six miRNAs, differentiated PCa benign prostatic hyperplasia 100%. Notably, reached 90.6% classification metastatic nonmetastatic PCa. We envision that will promote adaptability biopsy.

Язык: Английский

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Distinct mesenchymal cell states mediate prostate cancer progression

Nature Communications, Год журнала: 2024, Номер 15(1)

Опубликована: Янв. 8, 2024

Abstract In the complex tumor microenvironment (TME), mesenchymal cells are key players, yet their specific roles in prostate cancer (PCa) progression remain to be fully deciphered. This study employs single-cell RNA sequencing delineate molecular changes stroma that influence PCa and metastasis. Analyzing from four genetically engineered mouse models (GEMMs) correlating these findings with human tumors, we identify eight stromal cell populations distinct transcriptional identities consistent across both species. Notably, signatures advanced disease reflect those bone metastases, highlighting periostin’s role invasion differentiation. From insights, derive a gene signature predicts metastatic localized beyond traditional Gleason scores. Our results illuminate critical of dynamics on progression, suggesting new prognostic tools therapeutic targets.

Язык: Английский

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Active DHEA uptake in the prostate gland correlates with aggressive prostate cancer

Journal of Clinical Investigation, Год журнала: 2023, Номер 133(24)

Опубликована: Дек. 14, 2023

Strategies for patient stratification and early intervention are required to improve clinical benefits patients with prostate cancer. Here, we found that active DHEA utilization in the gland correlated tumor aggressiveness at disease stages, 3βHSD1 inhibitors were promising intervention. [3H]-labeled consumption was traced fresh prostatic biopsies ex vivo. Active more frequently metastatic or therapy-resistant disease. Genetic transcriptomic features associated potency of analyzed generate clinically accessible approaches stratification. UBE3D, by regulating homeostasis, discovered be a regulator metabolic heterogeneity. Equilin suppressed inhibited growth as potent antagonist, providing strategy treatment aggressive Overall, our findings indicate might benefit from

Язык: Английский

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Mutations found in cancer patients compromise DNA binding of the winged helix protein STK19

Scientific Reports, Год журнала: 2024, Номер 14(1)

Опубликована: Июнь 18, 2024

Abstract Serine/threonine protein kinase 19 (STK19) has been reported to phosphorylate and activate oncogenic NRAS promote melanomagenesis. However, concerns have raised about whether STK19 is a kinase. also identified as putative factor involved in the transcription-coupled nucleotide excision repair (TC-NER) pathway. In this study, we determined 1.32 Å crystal structure of human STK19. The reveals that winged helix (WH) consisting three tandem WH domains. binds more strongly double-stranded DNA RNA (dsDNA/dsRNA) than ssDNA. A positively charged patch centered on WH3-H1 contributes dsDNA binding, which unusual because domain typically uses H3 recognition helix. Importantly, mutations conserved residues basic patch, K186N, R200W, R215W, are found cancer patients, these compromise binding. Other predicted produce similar effect, including two disrupt nuclear localization signal (NLS) motif. These may indirectly impact binding capacity by interfering with its localization.

Язык: Английский

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Genome-wide interrogation of structural variation reveals novel African-specific prostate cancer oncogenic drivers

Genome Medicine, Год журнала: 2022, Номер 14(1)

Опубликована: Авг. 31, 2022

Abstract Background African ancestry is a significant risk factor for advanced prostate cancer (PCa). Mortality rates in sub-Saharan Africa are 2.5-fold greater than global averages. However, the region has largely been excluded from benefits of whole genome interrogation studies. Additionally, while structural variation (SV) highly prevalent, PCa genomic studies still biased towards small variant interrogation. Methods Using sequencing and best practice workflows, we performed comprehensive analysis SVs 180 (predominantly Gleason score ≥ 8) tumours derived 115 African, 61 European four ancestrally admixed patients. We investigated landscape relationship somatic driving ethnic disparity (African versus European), with focus on men southern Africa. Results Duplication events showed greatest disparity, 1.6- (relative frequency) to (count) increase African-derived tumours. Furthermore, found duplication be associated CDK12 inactivation MYC copy number gain, deletion SPOP mutation. Overall, were 2-fold more likely present hyper-SV subtype. In addition hyper-duplication subtypes, describe new hyper-translocation While confirm lower TMPRSS2-ERG fusion-positive rate cases (10% 33%), novel African-specific ETS family member TMPRSS2 fusion partners identified, including LINC01525, FBXO7 , GTF3C2 NTNG1 YPEL5 . Notably, 74 SV hotspots impacting 18 candidate driver genes, CADM2 LSAMP PTPRD PDE4D PACRG having therapeutic implications Conclusions this first African-inclusive study high-risk PCa, demonstrate power identification oncogenic drivers targets. Identifying spectrum patients provides mechanism that may contribute, at least part, observed presentation ancestry.

Язык: Английский

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Prostate cancer genetic risk and associated aggressive disease in men of African ancestry

Nature Communications, Год журнала: 2023, Номер 14(1)

Опубликована: Дек. 5, 2023

African ancestry is a significant risk factor for prostate cancer and advanced disease. Yet, genetic studies have largely been conducted outside the context of Sub-Saharan Africa, identifying 278 common variants contributing to multiethnic polygenic score, with rare focused on panel roughly 20 pathogenic genes. Based this knowledge, we are unable determine or differentiate status interrogating whole genome data 113 Black South men. To further assess potentially functional variant associations, here interrogate 247,780 exomic 798 men using case versus control aggressive non-aggressive study design. Notable genes interest include HCP5, RFX6 H3C1 risk, MKI67 KLF5 Our highlights need inclusion across diaspora establish African-relevant models aimed at reducing health disparities.

Язык: Английский

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Racism Does Not Cause Prostate Cancer, It Causes Prostate Cancer Death

Journal of Clinical Oncology, Год журнала: 2023, Номер 41(12), С. 2151 - 2154

Опубликована: Янв. 24, 2023

Язык: Английский

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A novel prostate cancer subtyping classifier based on luminal and basal phenotypes

Cancer, Год журнала: 2023, Номер 129(14), С. 2169 - 2178

Опубликована: Апрель 14, 2023

Abstract Background Prostate cancer (PCa) is a clinically heterogeneous disease. The creation of an expression‐based subtyping model based on prostate‐specific biological processes was sought. Methods Unsupervised machine learning gene expression profiles from prospectively collected primary prostate tumors (training, n = 32,000; evaluation, 68,547) used to create classifier (PSC) basal versus luminal cell patterns and other signatures relevant PCa biology. Subtype molecular pathways clinical characteristics were explored in five cohorts. Results Clustering derived four subtypes: differentiated (LD), proliferating (LP), immune (BI), neuroendocrine (BN). LP LD both had higher androgen receptor activity. also proliferation genes, MYC activity, homologous recombination deficiency. BI possessed significant interferon γactivity infiltration immunohistochemistry. BN characterized by lower activity expression, infiltration, enrichment with patterns. Patients less aggressive tumor the longest time metastasis after surgery. Only patients benefit radiotherapy surgery terms (hazard ratio [HR], 0.09; 95% CI, 0.01–0.71; 855). In phase 3 trial that randomized metastatic deprivation or without docetaxel ( 108), only survival (HR, 0.21; 0.09–0.51). Conclusions With use over 100,000 tumors, PSC developed identified subtypes distinct features. Plain language summary can behave indolent manner vary how it responds certain treatments. To differentiate basis features, we novel RNA signature using data tumors—the largest set its kind. This inform physicians aggressiveness susceptibilities treatments help personalize management.

Язык: Английский

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Health Equity Research Outcomes and Improvement Consortium Prostate Cancer Health Precision Africa1K: Closing the Health Equity Gap Through Rural Community Inclusion

Journal of Urologic Oncology, Год журнала: 2024, Номер 22(2), С. 144 - 149

Опубликована: Июль 29, 2024

Prostate cancer shows significant racial disparity, with men of African ancestry disproportionately impacted. While prostate health disparity studies focus on elucidating the contributing socioeconomic, lifestyle, environmental, biological and underlying genetic factors, genome sequencing is helping to reduce burden through disease stratification treatment. Sub-Saharan Africa has, till now, been excluded from these benefits. The new Cancer Precision Health Africa1K Equity Research Outcomes Improvement Consortium has tasked addressing this gap. Initiating efforts in Southern Africa, highest globally recorded regional mortality rates, review we discuss our earliest observations, objective share knowledge, encourage further inclusivity across while considering challenges Most notably, contrast regions current scientific efforts, nations not only represent extreme disparities rural-urban transition, but early data also suggests that transition direct impact both nongenetic determinants, translation into tumour disparities. Ultimately, propose first-of-its-kind resource, rural communities provide an unmet opportunity control for cultural practices, movement, ancestry, environmental exposures enhance inclusion studies.

Язык: Английский

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Common Genetic Variants Associated with Prostate Cancer Risk: The Need for African Inclusion

European Urology, Год журнала: 2023, Номер 84(1), С. 22 - 24

Опубликована: Апрель 24, 2023

Язык: Английский

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