Applications of single-cell RNA sequencing in drug discovery and development

Nature Reviews Drug Discovery, Journal Year: 2023, Volume and Issue: 22(6), P. 496 - 520

Published: April 28, 2023

Single-cell technologies, particularly single-cell RNA sequencing (scRNA-seq) methods, together with associated computational tools and the growing availability of public data resources, are transforming drug discovery development. New opportunities emerging in target identification owing to improved disease understanding through cell subtyping, highly multiplexed functional genomics screens incorporating scRNA-seq enhancing credentialling prioritization. ScRNA-seq is also aiding selection relevant preclinical models providing new insights into mechanisms action. In clinical development, can inform decision-making via biomarker for patient stratification more precise monitoring response progression. Here, we illustrate how methods being applied key steps discuss ongoing challenges their implementation pharmaceutical industry. There have been significant recent advances development remarkable Ferran colleagues primarily pipeline, from decision-making. Ongoing potential future directions discussed.

Language: Английский

---

Dissecting the immune suppressive human prostate tumor microenvironment via integrated single-cell and spatial transcriptomic analyses

Nature Communications, Journal Year: 2023, Volume and Issue: 14(1)

Published: Feb. 7, 2023

The treatment of low-risk primary prostate cancer entails active surveillance only, while high-risk disease requires multimodal including surgery, radiation therapy, and hormonal therapy. Recurrence development metastatic remains a clinical problem, without clear understanding what drives immune escape tumor progression. Here, we comprehensively describe the microenvironment localized in comparison with adjacent normal samples healthy controls. Single-cell RNA sequencing high-resolution spatial transcriptomic analyses reveal context dependent changes gene expression. Our data indicate that an suppressive associates myeloid populations exhausted T-cells, addition to high stromal angiogenic activity. We infer cell-to-cell relationships from throughput ligand-receptor interaction measurements within undissociated tissue sections. work thus provides highly detailed comprehensive resource as well tumor-stromal cell interactions.

Language: Английский

---

Ectopic JAK–STAT activation enables the transition to a stem-like and multilineage state conferring AR-targeted therapy resistance

Nature Cancer, Journal Year: 2022, Volume and Issue: 3(9), P. 1071 - 1087

Published: Sept. 5, 2022

Emerging evidence indicates that various cancers can gain resistance to targeted therapies by acquiring lineage plasticity. Although genomic and transcriptomic aberrations correlate with plasticity, the molecular mechanisms enabling acquisition of plasticity have not been fully elucidated. We reveal Janus kinase (JAK)-signal transducer activator transcription (STAT) signaling is a crucial executor in promoting plasticity-driven androgen receptor (AR)-targeted therapy prostate cancer. Importantly, ectopic JAK-STAT activation specifically required for stem-like subclones expressing multilineage transcriptional programs but exclusively neuroendocrine-like program. Both genetic pharmaceutical inhibition resensitizes resistant tumors AR-targeted therapy. Together, these results suggest are compelling therapeutic targets overcoming resistance.

Language: Английский

---

Single cell analysis of cribriform prostate cancer reveals cell intrinsic and tumor microenvironmental pathways of aggressive disease

Nature Communications, Journal Year: 2022, Volume and Issue: 13(1)

Published: Oct. 13, 2022

Abstract Cribriform prostate cancer, found in both invasive cribriform carcinoma (ICC) and intraductal (IDC), is an aggressive histological subtype that associated with progression to lethal disease. To delineate the molecular cellular underpinnings of ICC/IDC aggressiveness, this study examines paired benign surgical samples by single-cell RNA-sequencing, TCR sequencing, histology. cancer cells express genes metastasis targets potential for therapeutic intervention. Pathway analyses ligand/receptor status model interactions among tumor microenvironment (TME) including JAG1/NOTCH. The TME hallmarked increased angiogenesis immunosuppressive fibroblasts ( CTHRC1 + ASPN FAP ENG ) along fewer T cells, elevated cell dysfunction, C1QB TREM2 APOE -M2 macrophages. These findings support intrinsic pathways a complex contribute phenotype ICC/IDC. data highlight opportunities restore immune signaling patients may afford better outcomes.

Language: Английский

---

Targeting myeloid chemotaxis to reverse prostate cancer therapy resistance

Nature, Journal Year: 2023, Volume and Issue: 623(7989), P. 1053 - 1061

Published: Oct. 16, 2023

Abstract Inflammation is a hallmark of cancer 1 . In patients with cancer, peripheral blood myeloid expansion, indicated by high neutrophil-to-lymphocyte ratio, associates shorter survival and treatment resistance across malignancies therapeutic modalities 2–5 Whether inflammation drives progression prostate in humans remain unclear. Here we show that inhibition chemotaxis can reduce tumour-elicited reverse therapy subset metastatic castration-resistant (CRPC). We higher ratio reflects tumour infiltration expression senescence-associated mRNA species, including those encode myeloid-chemoattracting CXCR2 ligands. To determine whether cells fuel to androgen receptor signalling inhibitors, inhibiting block reverses this, conducted an investigator-initiated, proof-of-concept clinical trial inhibitor (AZD5069) plus enzalutamide CRPC resistant inhibitors. This combination was well tolerated without dose-limiting toxicity it decreased circulating neutrophil levels, reduced intratumour CD11b + HLA-DR lo CD15 CD14 − cell imparted durable benefit biochemical radiological responses CRPC. study provides evidence blockade. Targeting merits broader evaluation other cancers.

Language: Английский

---

The implications of single-cell RNA-seq analysis in prostate cancer: unraveling tumor heterogeneity, therapeutic implications and pathways towards personalized therapy

Military Medical Research, Journal Year: 2024, Volume and Issue: 11(1)

Published: April 11, 2024

Abstract In recent years, advancements in single-cell and spatial transcriptomics, which are highly regarded developments the current era, particularly emerging integration of spatiotemporal have enabled a detailed molecular comprehension complex regulation cell fate. The insights obtained from these methodologies anticipated to significantly contribute development personalized medicine. Currently, technology is less frequently utilized for prostate cancer compared with other types tumors. Starting perspective RNA sequencing technology, this review outlined significance (scRNA-seq) research, encompassing preclinical medicine clinical applications. We summarize differences between mouse human as revealed by scRNA-seq studies, well combination multi-omics methods involving highlight key targets diagnosis, treatment, drug resistance characteristics cancer. These studies expected provide novel immunotherapy innovative treatment strategies castration-resistant Furthermore, we explore potential applications stemming technologies review, paving way future research precision

Language: Английский

---

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

---

Spatial landscapes of cancers: insights and opportunities

Nature Reviews Clinical Oncology, Journal Year: 2024, Volume and Issue: 21(9), P. 660 - 674

Published: July 23, 2024

Language: Английский

---

Anti-PD-1 immunotherapy with androgen deprivation therapy induces robust immune infiltration in metastatic castration-sensitive prostate cancer

Cancer Cell, Journal Year: 2023, Volume and Issue: 41(11), P. 1972 - 1988.e5

Published: Nov. 1, 2023

When compared to other malignancies, the tumor microenvironment (TME) of primary and castration-resistant prostate cancer (CRPC) is relatively devoid immune infiltrates. While androgen deprivation therapy (ADT) induces a complex infiltrate in localized cancer, composition TME metastatic castration-sensitive (mCSPC), effects ADT treatments this context are poorly understood. Here, we perform comprehensive single-cell RNA sequencing (scRNA-seq) profiling sites from patients participating phase 2 clinical trial (NCT03951831) that evaluated standard-of-care chemo-hormonal combined with anti-PD-1 immunotherapy. We longitudinal, protein activity-based analysis subpopulations, revealing subpopulations conserved across multiple sites. also observe dynamic changes these response treatment correlation outcomes. Our study uncovers therapy-resistant, transcriptionally distinct subpopulation expands cell number treatment-refractory patients.

Language: Английский

---

YAP1 Inhibition Induces Phenotype Switching of Cancer-Associated Fibroblasts to Tumor Suppressive in Prostate Cancer

Cancer Research, Journal Year: 2024, Volume and Issue: 84(22), P. 3728 - 3742

Published: Aug. 13, 2024

Prostate cancer rarely responds to immune-checkpoint blockade (ICB) therapies. Cancer-associated fibroblasts (CAF) are critical components of the immunologically "cold" tumor microenvironment and considered a promising target enhance immunotherapy response. In this study, we aimed reveal mechanisms regulating CAF plasticity identify potential strategies switch CAFs from protumorigenic antitumor phenotypes ICB efficacy in prostate cancer. Integration four single-cell RNA sequencing datasets defined CAFs, RNA-seq, flow cytometry, organoid model demonstrated functions two subtypes. Extracellular matrix-associated (ECM-CAF) promoted collagen deposition cell progression, lymphocyte-associated (Lym-CAF) exhibited an phenotype induced infiltration activation CD8+ T cells. YAP1 activity regulated ECM-CAF phenotype, silencing switching Lym-CAFs. NF-κB p65 was core transcription factor Lym-CAF subset, inhibited nuclear translocation p65. Selective depletion ECM-CAFs vivo T-cell enhanced therapeutic effects anti-PD-1 treatment on Overall, study revealed mechanism identity highlighted strategy for altering subtype suppress growth increase sensitivity ICB. Significance: regulates cancer-associated fibroblast can be targeted that promotes extracellular matrix tumor-suppressive stimulates immunity efficacy.

Language: Английский

---