High-grade serous tubo-ovarian cancer refined with single-cell RNA sequencing: specific cell subtypes influence survival and determine molecular subtype classification

Genome Medicine, Journal Year: 2021, Volume and Issue: 13(1)

Published: July 8, 2021

High-grade serous tubo-ovarian cancer (HGSTOC) is characterised by extensive inter- and intratumour heterogeneity, resulting in persistent therapeutic resistance poor disease outcome. Molecular subtype classification based on bulk RNA sequencing facilitates a more accurate characterisation of this but the lack strong prognostic or predictive correlations with these subtypes currently hinders their clinical implementation. Stromal admixture profoundly affects impact molecular subtypes, contribution stromal cells to each has poorly been characterised. Increasing transcriptomic resolution single-cell (scRNA-seq) may provide insights relevance subtypes.We performed scRNA-seq 18,403 unbiasedly collected from 7 treatment-naive HGSTOC tumours. For phenotypic cluster tumour cells, we identified specific markers. We explored which clusters correlated overall survival expression markers microarray data 1467 By evaluating signatures single assessed what extent contributes subtype.We 11 32 cell phenotypes Of these, relative frequency myofibroblasts, TGF-β-driven cancer-associated fibroblasts, mesothelial lymphatic endothelial predicted outcome, while plasma favourable Moreover, clear cell-like signature worse patients. differed substantially between subtypes. instance, mesenchymal, immunoreactive differentiated were fibroblast, immune myofibroblast/mesothelial phenotypes, respectively. Cell correlating outcome enriched associated outcome.We used identify predicting These features explain association also latter's weakness Stratifying patients marker genes for represents promising approach predict prognosis response therapy.

Language: Английский

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Single-cell transcriptomic analysis of endometriosis

Nature Genetics, Journal Year: 2023, Volume and Issue: 55(2), P. 255 - 267

Published: Jan. 9, 2023

Language: Английский

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Neoadjuvant PARPi or chemotherapy in ovarian cancer informs targeting effector Treg cells for homologous-recombination-deficient tumors

Cell, Journal Year: 2024, Volume and Issue: 187(18), P. 4905 - 4925.e24

Published: July 5, 2024

Homologous recombination deficiency (HRD) is prevalent in cancer, sensitizing tumor cells to poly (ADP-ribose) polymerase (PARP) inhibition. However, the impact of HRD and related therapies on microenvironment (TME) remains elusive. Our study generates single-cell gene expression T cell receptor profiles, along with validatory multimodal datasets from >100 high-grade serous ovarian cancer (HGSOC) samples, primarily a phase II clinical trial (NCT04507841). Neoadjuvant monotherapy PARP inhibitor (PARPi) niraparib achieves impressive 62.5% 73.6% response rates per RECIST v.1.1 GCIG CA125, respectively. We identify effector regulatory (eTregs) as key responders neoadjuvant therapies, co-occurring other tumor-reactive cells, particularly terminally exhausted CD8+ (Tex). TME-wide interferon signaling correlates upregulating MHC class co-inhibitory ligands, potentially driving Treg Tex fates. Depleting eTregs mouse models, or without inhibition, significantly suppresses growth observable toxicities, underscoring potential eTreg-focused therapeutics for HGSOC HRD-related tumors.

Language: Английский

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A cell atlas of the human fallopian tube throughout the menstrual cycle and menopause

Nature Communications, Journal Year: 2025, Volume and Issue: 16(1)

Published: Jan. 3, 2025

The fallopian tube undergoes extensive molecular changes during the menstrual cycle and menopause. We use single-cell RNA ATAC sequencing to construct a comprehensive cell atlas of healthy human tubes Our scRNA-seq comparison 85,107 pre- 46,111 post-menopausal cells reveals substantial shifts in type frequencies, gene expression, transcription factor activity, cell-to-cell communications menopause cycle. Menstrual dependent hormonal regulate distinct states secretory epithelial cells. Postmenopausal show high chromatin accessibility factors associated with aging such as Jun, Fos, BACH1/2, while hormone receptors were generally downregulated, small proportion had expression ESR2, IGF1R, LEPR. While pre-menopausal cluster is enriched immunoreactive subtype, subset genes expressed enrichment mesenchymal high-grade serous ovarian cancer. cellular aging. Here, Weigert et al. present normal revealing transition throughout

Language: Английский

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Single-cell analysis of menstrual endometrial tissues defines phenotypes associated with endometriosis

BMC Medicine, Journal Year: 2022, Volume and Issue: 20(1)

Published: Sept. 15, 2022

Abstract Background Endometriosis is a common, complex disorder which underrecognized and subject to prolonged delays in diagnosis. It accompanied by significant changes the eutopic endometrial lining. Methods We have undertaken first single-cell RNA-sequencing (scRNA-Seq) comparison of tissues freshly collected menstrual effluent (ME) from 33 subjects, including confirmed endometriosis patients (cases) controls as well symptomatic subjects (who chronic symptoms suggestive but not been diagnosed). Results identify unique subcluster proliferating uterine natural killer (uNK) cells ME-tissues that almost absent cases, along with striking reduction total uNK ME cases ( p < 10 −16 ). In addition, an IGFBP1+ decidualized subset stromal are abundant shed endometrium when compared ) confirming findings compromised decidualization cultured cases. By contrast, enriched expressing pro-inflammatory senescent phenotypes. An enrichment B = 5.8 × −6 raises possibility some may endometritis, predisposes endometriosis. Conclusions propose characterization will provide effective screening tool for identifying this disorder. This constitutes major advance, since delayed diagnosis many years clinical problem evaluation these patients. Comprehensive analysis expected lead new diagnostic therapeutic approaches other associated reproductive disorders such female infertility.

Language: Английский

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A multi-level investigation of the genetic relationship between endometriosis and ovarian cancer histotypes

Cell Reports Medicine, Journal Year: 2022, Volume and Issue: 3(3), P. 100542 - 100542

Published: March 1, 2022

Language: Английский

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Cellular heterogeneity of human fallopian tubes in normal and hydrosalpinx disease states identified using scRNA-seq

Developmental Cell, Journal Year: 2022, Volume and Issue: 57(7), P. 914 - 929.e7

Published: March 22, 2022

Language: Английский

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The transcription factor PAX8 promotes angiogenesis in ovarian cancer through interaction with SOX17

Science Signaling, Journal Year: 2022, Volume and Issue: 15(728)

Published: April 5, 2022

PAX8 is a master transcription factor that essential during embryogenesis and promotes neoplastic growth. It expressed by the secretory cells lining female reproductive tract, its deletion development results in atresia of tract organs. Nearly all ovarian carcinomas express PAX8, knockdown apoptosis cancer cells. To explore role these tissues, we purified protein complex from nonmalignant fallopian tube high-grade serous carcinoma cell lines. We found was member large chromatin remodeling preferentially interacted with SOX17, another developmental factor. Depleting either or SOX17 altered expression factors involved angiogenesis functionally disrupted tubule capillary formation culture mouse models. promoted secretion angiogenic suppressing SERPINE1 , which encodes proteinase inhibitor anti ngiogenic effects. The findings reveal non–cell-autonomous function regulating cancer.

Language: Английский

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Single-cell transcriptome analysis of epithelial, immune, and stromal signatures and interactions in human ovarian cancer

Communications Biology, Journal Year: 2024, Volume and Issue: 7(1)

Published: Jan. 26, 2024

Abstract A comprehensive investigation of ovarian cancer (OC) progression at the single-cell level is crucial for enhancing our understanding disease, as well development better diagnoses and treatments. Here, over half a million transcriptome data were collected from 84 OC patients across all clinical stages. Through integrative analysis, we identified heterogeneous epithelial-immune-stromal cellular compartments their interactions in microenvironment. The epithelial cells displayed subtype features with functional variance. significant increase distinct T cell subtypes was including Tregs CD8+ exhausted stage IC2. Additionally, discovered antigen-presenting cancer-associated fibroblasts (CAFs), myofibroblastic CAFs (myCAFs) exhibiting enriched extracellular matrix (ECM) functionality linked to tumor Furthermore, NECTIN2-TIGIT ligand-receptor pair mediate communicating epithelial, fibroblast, endothelial, other types. Knock-out NECTIN2 using CRISPR/Cas9 inhibited (SKOV3) proliferation, increased proliferation when co-cultured. These findings shed light on aspects OC, providing insights into molecular mechanisms underlying IC2 potential therapeutic strategies OC.

Language: Английский

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Characterization of the human fetal gonad and reproductive tract by single-cell transcriptomics

Developmental Cell, Journal Year: 2024, Volume and Issue: 59(4), P. 529 - 544.e5

Published: Jan. 30, 2024

During human fetal development, sex differentiation occurs not only in the gonads but also adjacent developing reproductive tract. However, while cellular composition of male and female is well described, that tract remains poorly characterized. Here, we performed single-cell transcriptomics on together with from first second trimesters, highlighting morphological molecular changes during differentiation. We validated different cell populations compared signatures between as sexes, to identify conserved sex-specific features. Together, our study provides insights into gonadogenesis development beyond gonads.

Language: Английский

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