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| Open AccessVOLTA: an enVironment-aware cOntrastive ceLl represenTation leArning for histopathology
While machine learning platforms can improve the assessment of Hematoxylin & Eosin (H&E) stained-tumour tissue images, current models typically require manual cell-type annotations in training. Here, the authors develop VOLTA, a self-supervised machine learning framework to improve cell representation learning in H&E images based on the cells environment
- Ramin Nakhli
- , Katherine Rich
- & Ali Bashashati
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Article
| Open AccessSpatial transcriptomics reveals discrete tumour microenvironments and autocrine loops within ovarian cancer subclones
Intratumoural heterogeneity in high-grade serous ovarian carcinoma (HGSOC) remains to be explored. Here, the authors perform spatial transcriptomics and reveal a high degree of subclonal heterogeneity in HGSOC.
- Elena Denisenko
- , Leanne de Kock
- & Alistair R. R. Forrest
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| Open AccessTargeting branched N-glycans and fucosylation sensitizes ovarian tumors to immune checkpoint blockade
Cancer cells can employ aberrant glycosylation patterns to evade the host immune response. Here the authors report that inhibition of branched N-glycans sensitizes homologous recombination (HR)-proficient, but not HR-deficient, epithelial ovarian cancer to immune checkpoint inhibitors.
- Hao Nie
- , Pratima Saini
- & Rugang Zhang
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| Open AccessThe CHK1 inhibitor prexasertib in BRCA wild-type platinum-resistant recurrent high-grade serous ovarian carcinoma: a phase 2 trial
ATR/CHK1 pathway inhibitors represent a therapeutic option for platinum-resistant high-grade serous ovarian carcinoma (HGSOC). Here the authors report the results of a phase 2 clinical study of the CHK1 inhibitor prexasertib in patients with BRCA wild-type platinum-resistant HGSOC with or without biopsiable disease.
- Elena Giudice
- , Tzu-Ting Huang
- & Jung-Min Lee
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Article
| Open AccessTertiary lymphoid structures and B cells determine clinically relevant T cell phenotypes in ovarian cancer
Intratumoral tertiary lymphoid structure (TLS) density has been associated with better prognosis in several cancer types. Here the authors provide a comprehensive characterization of TLSs in patients with high-grade serous ovarian carcinoma.
- Lenka Kasikova
- , Jana Rakova
- & Jitka Fucikova
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| Open AccessComprehensive multi-omics analysis reveals WEE1 as a synergistic lethal target with hyperthermia through CDK1 super-activation
The benefit of hyperthermic intraperitoneal chemotherapy in epithelial ovarian cancer remains controversial. Here, the authors perform a multi-omics analysis of hyperthermia-treated ovarian cancer cells, show that CDK1 becomes hyperactivated and regulates signalling upon hyperthermia, and identify WEE1 as a synergistic therapeutic target for hyperthermic intraperitoneal therapy.
- Xiaohang Yang
- , Xingyuan Hu
- & Chaoyang Sun
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Article
| Open AccessBevacizumab, olaparib, and durvalumab in patients with relapsed ovarian cancer: a phase II clinical trial from the GINECO group
Prognosis for patients diagnosed with advanced stage ovarian cancer remains poor. Here the authors report the results of a phase 2 study of a triple combination of the PARP inhibitor olaparib in combination with durvalumab (anti-PD1) and bevacizumab (antiVEGF) in advanced ovarian cancer.
- Gilles Freyer
- , Anne Floquet
- & Michele Lamuraglia
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| Open AccessAggresome formation promotes ASK1/JNK signaling activation and stemness maintenance in ovarian cancer
The role of aggresomes in tumorigenesis and cancer progression remains to be explored. Here, the authors perform multi-omics and reveal that aggresome formation supports ovarian cancer stem cell properties via OTUD1 and ASK1/JNK signalling activation.
- Yurou Chen
- , Yulong Qiang
- & Feng Li
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Article
| Open AccessResidual ANTXR1+ myofibroblasts after chemotherapy inhibit anti-tumor immunity via YAP1 signaling pathway
An important contribution of cancer associated fibroblasts (CAFs) in regulating chemoresistance has been reported. Here the authors investigate the impact of chemotherapy on CAF subsets in patients with high-grade serous ovarian cancer, suggesting that residual ANTXR1+ myofibroblasts are associated with inhibition of anti-tumor immunity.
- Monika Licaj
- , Rana Mhaidly
- & Fatima Mechta-Grigoriou
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Article
| Open AccessTracing back primed resistance in cancer via sister cells
Transcriptional cell states can drive treatment resistance in cancer. Here, the authors develop ReSisTrace to predict cell states that are primed to resist ovarian cancer treatment and validate their findings using small molecule inhibitors.
- Jun Dai
- , Shuyu Zheng
- & Anna Vähärautio
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Article
| Open AccessProteomic characterization of epithelial ovarian cancer delineates molecular signatures and therapeutic targets in distinct histological subtypes
The molecular phenotypic features of epithelial ovarian cancer (EOC) remain elusive. Here, the authors perform mass spectrometry-based proteomic profiling for 269 EOC patients and reveal molecularly distinct features and potential therapeutic targets among the histological subtypes of EOC.
- Ting-Ting Gong
- , Shuang Guo
- & Qi-Jun Wu
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| Open AccessDetection of isoforms and genomic alterations by high-throughput full-length single-cell RNA sequencing in ovarian cancer
Long-read single-cell RNA sequencing is capable of detecting isoform-level gene expression and genomic alterations such as mutations and gene fusions, thereby providing cell-specific genotype-phenotype information. Here, the authors use long-read scRNA-seq on metastatic ovarian cancer samples and detect cell-type specific isoforms and gene fusions that may otherwise be misclassified in short-read data.
- Arthur Dondi
- , Ulrike Lischetti
- & Niko Beerenwinkel
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| Open AccessRepression of LSD1 potentiates homologous recombination-proficient ovarian cancer to PARP inhibitors through down-regulation of BRCA1/2 and RAD51
Here, the authors identify lysine-specific demethylase 1 is a homologous recombination (HR) regulator. Its inhibitor induces HR deficiency and sensitizes HR-proficient ovarian cancer cells to PARP inhibitors, which expand the use of PARP inhibitors.
- Lei Tao
- , Yue Zhou
- & Yinglan Zhao
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| Open AccessUnlocking the potential of allogeneic Vδ2 T cells for ovarian cancer therapy through CD16 biomarker selection and CAR/IL-15 engineering
Vγ9Vδ2 (Vδ2) T cells have been proposed as cell carriers for off-the-shelf CAR therapies. Here the authors describe CD16 as a biomarker for the selection of Vδ2 T cells with high levels of cytotoxicity and report the anti-tumor activity of engineered CD16high Vδ2 T cells in ovarian cancer preclinical models.
- Derek Lee
- , Zachary Spencer Dunn
- & Lili Yang
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Article
| Open AccessSpatial exosome analysis using cellulose nanofiber sheets reveals the location heterogeneity of extracellular vesicles
Extracellular vesicles (EVs) are known to be heterogeneous intravitally. Here, we present cellulose nanofiber sheets which capture EVs with high purity from trace volumes of biofluids and enable analysis of location-dependent heterogeneity to enhance understanding of pathological mechanisms and enable diagnostic readouts.
- Akira Yokoi
- , Kosuke Yoshida
- & Takao Yasui
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Article
| Open AccessIntegrated radiogenomics models predict response to neoadjuvant chemotherapy in high grade serous ovarian cancer
Response to treatment in high grade serous ovarian carcinoma (HGSOC) is highly variable. Here, the authors leverage a radiogenomic model to predict neoadjuvant chemotherapy response in HGSOC, including clinical data, medical imaging, and blood-based biomarkers such as CA-125 and ctDNA features.
- Mireia Crispin-Ortuzar
- , Ramona Woitek
- & James D. Brenton
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Article
| Open AccessMolecular landscape and functional characterization of centrosome amplification in ovarian cancer
The prevalence of centrosome amplification (CA) and the genomic landscape of chromosomal instability in high-grade serous ovarian carcinoma (HGSOC) remain to be explored. Here the authors suggest CA as a potential driver of tumour evolution and a biomarker for treatment response in HGSOC.
- Carolin M. Sauer
- , James A. Hall
- & James D. Brenton
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| Open AccessTriplet maintenance therapy of olaparib, pembrolizumab and bevacizumab in women with BRCA wild-type, platinum-sensitive recurrent ovarian cancer: the multicenter, single-arm phase II study OPEB-01/APGOT-OV4
Even in patients who are initially sensitive, patients treated with platinum-based therapies often go on to relapse and have limited treatment options. Here, the authors report the efficacy and safety of a phase II trial investigating olaparib, pembrolizumab and bevacizumab as maintenance therapy in platinum-sensitive recurrent ovarian cancer.
- Yoo-Na Kim
- , Boram Park
- & Jung-Yun Lee
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| Open AccessThe copy number and mutational landscape of recurrent ovarian high-grade serous carcinoma
‘Treatment resistance is common in ovarian high grade serous carcinoma, often leading to relapse. Here, the authors leverage shallow whole genome and panel sequencing of 276 patients with available diagnostic and relapse samples and show high concordance of copy number and mutation status.
- Philip Smith
- , Thomas Bradley
- & Iain A. McNeish
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Article
| Open AccessNivolumab plus chemoradiotherapy in locally-advanced cervical cancer: the NICOL phase 1 trial
A combination of chemoradiotherapy followed by brachytherapy is recommended for patients with locally-advanced cervical cancer (LACC), however there is still a high risk of disease recurrence. Here the authors report clinical outcomes and immunologic correlates of a clinical trial of the PD-1 inhibitor nivolumab in combination with chemoradiotherapy in LACC patients.
- Manuel Rodrigues
- , Giulia Vanoni
- & Emanuela Romano
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| Open AccessExtracellular matrix educates an immunoregulatory tumor macrophage phenotype found in ovarian cancer metastasis
Although remodelling of the extracellular matrix (ECM) is associated with the establishment of an immunosuppressive tumour microenvironment, whether the ECM can educate tumor-associated macrophage phenotypes is not known. Here, the authors examine this question using decellularized tissue models of omental metastasis from patient biopsies.
- E. H. Puttock
- , E. J. Tyler
- & O. M. T. Pearce
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Article
| Open AccessSingle cell transcriptomic analysis of HPV16-infected epithelium identifies a keratinocyte subpopulation implicated in cancer
The role of keratinocyte subpopulations in the different phases of the viral cycle during HPV16 infection remains to be characterised. Here, single cell RNA sequencing of HPV16 infected and uninfected organoids identifies 12 distinct keratinocyte populations including an HPV-reprogrammed keratinocyte subpopulation that is linked to cancer.
- Mary C. Bedard
- , Tafadzwa Chihanga
- & Susanne I. Wells
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| Open AccessClinical outcome and biomarker assessments of a multi-centre phase II trial assessing niraparib with or without dostarlimab in recurrent endometrial carcinoma
Treatment options in patients with recurrent endometrial carcinoma (EC) are limited and response rates to chemotherapy are poor. Here the authors report the results of a phase II trial of niraparib (PARP inhibitor) monotherapy or in combination with dostarlimab (anti-PD1) in recurrent EC.
- Ainhoa Madariaga
- , Swati Garg
- & Stephanie Lheureux
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| Open AccessReconstructing clonal tree for phylo-phenotypic characterization of cancer using single-cell transcriptomics
The functional changes of individual clones in single cell RNA sequencing (scRNA-seq) data remain elusive. Here, the authors develop PhylEx that integrates bulk genomics data with co-occurrences of mutations revealed by scRNA-seq data and apply it to high-grade serous ovarian cancer cell line and breast cancer datasets.
- Seong-Hwan Jun
- , Hosein Toosi
- & Jens Lagergren
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| Open AccessEvidence of a causal effect of genetic tendency to gain muscle mass on uterine leiomyomata
Many genetic factors that contribute to uterine leiomyomata (UL) - the most common tumours of the female genital tract - remain to be discovered. Here, the authors conduct a UL meta-genome-wide association study, and find loci related to altered muscle tissue biology that are associated with UL.
- Eeva Sliz
- , Jaakko S. Tyrmi
- & Johannes Kettunen
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| Open AccessA multicenter phase 2 trial of camrelizumab plus famitinib for women with recurrent or metastatic cervical squamous cell carcinoma
Patients with recurrent or metastatic cervical cancer have limited therapeutic options. Here the authors report efficacy and safety of camrelizumab (anti-PD-1 antibody) in combination with famitinib (anti-angiogenic agent) in pre-treated recurrent or metastatic squamous cervical cancer.
- Lingfang Xia
- , Qi Zhou
- & Xiaohua Wu
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| Open AccessAnalysis of matched primary and recurrent BRCA1/2 mutation-associated tumors identifies recurrence-specific drivers
Carriers of pathogenic BRCA1/2 variants have a higher risk of breast and ovarian cancers, which recur frequently. Here, the authors sequence primary and recurrent tumours of BRCA1/2 mutation carriers, finding PARP1 amplifications, differential BRCA2 isoform usage, and discordant loss of heterozygosity that are associated with recurrence.
- Jennifer B. Shah
- , Dana Pueschl
- & Katherine L. Nathanson
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| Open AccessClonal somatic copy number altered driver events inform drug sensitivity in high-grade serous ovarian cancer
Chromosomal instability is a major challenge to patient stratification and targeted drug development for high-grade serous ovarian carcinoma. Here we show that identification of clonal somatic copy number alterations in frequently amplified cancer genes could inform therapeutics for precision medicine.
- Filipe Correia Martins
- , Dominique-Laurent Couturier
- & James D. Brenton
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Article
| Open AccessSingle-cell transcriptomic analysis highlights origin and pathological process of human endometrioid endometrial carcinoma
Many aspects of the tumourigenesis of endometrioid endometrial cancers (EEC) are still poorly understood. Here, the authors use single-cell transcriptomics to characterise EEC tumours and their microenvironment across different stages, and reveal potential cells of origin for EEC.
- Xiaojun Ren
- , Jianqing Liang
- & Xiaojun Chen
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Article
| Open AccessHuman papillomavirus integration perspective in small cell cervical carcinoma
Small cell cervical carcinoma (SCCC) is a rare but aggressive malignancy. Here, the authors report human papillomavirus features and genomic landscape in SCCC via high-throughput sequencing methods and identify MYC, SOX, NR4A, ANKRD and CEA family genes as HPV-integrated hotspots.
- Xiaoli Wang
- , Wenlong Jia
- & Shuang Li
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| Open AccessIntegrated analysis of cervical squamous cell carcinoma cohorts from three continents reveals conserved subtypes of prognostic significance
Human papillomavirus (HPV) is a known cause of cervical cancer. Here, the authors perform a multi-omic analysis using published cervical squamous cell carcinoma cohorts from the USA, Europe, and SubSaharan Africa and identify two cervical squamous cell carcinoma subtypes that display prognostic differences.
- Ankur Chakravarthy
- , Ian Reddin
- & Tim R. Fenton
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| Open AccessSerine metabolism remodeling after platinum-based chemotherapy identifies vulnerabilities in a subgroup of resistant ovarian cancers
Metabolic reprogramming is associated with cancer development and therapy resistance. Here, the authors show that downregulation of the serine biosynthesis enzyme PHGDH in a fraction of patients is associated with relapse in platinum-treated ovarian cancers and to NAD+ and PARP activity upregulation.
- Tom Van Nyen
- , Mélanie Planque
- & Frédéric Amant
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| Open AccessA multi-omic dissection of super-enhancer driven oncogenic gene expression programs in ovarian cancer
Super-enhancers and their associated transcription factor networks have been shown to influence ovarian cancer biology. Here, based on an integrated set of genomic and epigenomic datasets, the authors identify clinically relevant super-enhancers amplified in ovarian cancer patients and functionally validate their activity.
- Michael R. Kelly
- , Kamila Wisniewska
- & Hector L. Franco
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Article
| Open AccessRevealing the human mucinome
Mucin-domain glycoproteins are densely O-glycosylated proteins with unique secondary structure that imparts a large influence on cellular environments. Here, the authors develop a technique to selectively enrich and characterize mucin-domain glycoproteins from cell lysate and patient biofluids.
- Stacy A. Malaker
- , Nicholas M. Riley
- & Carolyn R. Bertozzi
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| Open AccessLong-read sequencing unveils high-resolution HPV integration and its oncogenic progression in cervical cancer
The molecular mechanisms underlying cervical carcinogenesis following integration of HPV DNA into the human genome remain elusive. Here, the authors perform long-read sequencing in 16 HPV16-positive cervical tumors and identify distinct integration types, structural variations and potential driver genes.
- Liyuan Zhou
- , Qiongzi Qiu
- & Yan Lu
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Article
| Open AccessTertiary lymphoid structures critical for prognosis in endometrial cancer patients
Tertiary lymphoid structures (TLS) are associated with a reduced risk of cancer recurrence and improved response to immune checkpoint blockade in several tumor types. Here the authors identify L1CAM as a marker for mature TLS and show that the presence of TLS is associated with favorable prognosis in patients with endometrial cancer from the PORTEC-3 trial.
- Nanda Horeweg
- , Hagma H. Workel
- & Marco de Bruyn
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Article
| Open AccessSpatiotemporal dynamics of clonal selection and diversification in normal endometrial epithelium
Through regeneration, the endometrium accumulates somatic mutations that can lead to diseases like endometriosis and cancer. Here, the authors use genomics to analyse normal endometrial glands from different patient cohorts, detect rhizome structures with common clonal ancestors and infer clonal expansion dynamics.
- Manako Yamaguchi
- , Hirofumi Nakaoka
- & Takayuki Enomoto
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Article
| Open AccessSingle-cell tumor-immune microenvironment of BRCA1/2 mutated high-grade serous ovarian cancer
The tumour microenvironment has not been fully characterised in high-grade serous ovarian cancers (HGSOC). Here, the authors use highly multiplexed imaging to analyse the HGSOC immune microenvironment at spatial and single-cell resolution, with clinically relevant findings for BRCA1/2-mutated tumours.
- I.-M. Launonen
- , N. Lyytikäinen
- & A. Färkkilä
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Article
| Open AccessThe DNA methylome of cervical cells can predict the presence of ovarian cancer
Most ovarian cancers originate from cells originally derived from Müllerian Duct cells. Here, the authors show that the methylation profile of Müllerian Duct cells isolated from cervical samples can predict whether a woman has cervical cancer.
- James E. Barrett
- , Allison Jones
- & Martin Widschwendter
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Article
| Open AccessA Replication stress biomarker is associated with response to gemcitabine versus combined gemcitabine and ATR inhibitor therapy in ovarian cancer
A randomized phase 2 study recently showed that the addition of ATR inhibitor berzosertib to gemcitabine improved PFS compared to gemcitabine alone in patients with ovarian cancer. In this preplanned exploratory study, the authors demonstrate that a genomic biomarker of replication-stress is associated with outcome to gemcitabine alone and may predict which patients benefit from addition of the ATR inhibitor berzosertib.
- Panagiotis A. Konstantinopoulos
- , Alexandre André B. A. da Costa
- & Geoffrey I. Shapiro
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Article
| Open AccessClinically translatable quantitative molecular photoacoustic imaging with liposome-encapsulated ICG J-aggregates
Photoacoustic imaging is limited by a lack of contrast agents which can enable combined molecular and physiological imaging at depth. Here the authors address these limitations by developing and validating a contrast agent based on targeted liposomes loaded with J-aggregated indocyanine green dye.
- Cayla A. Wood
- , Sangheon Han
- & Richard R. Bouchard
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Article
| Open AccessTargeting the IRE1α/XBP1s pathway suppresses CARM1-expressing ovarian cancer
The unfolded protein response (UPR) promotes cell survival in cancers with hyperactive ER stress response. Here the authors show that CARM1, an arginine methyltransferase, controls the IRE1α/XBP1 pathway of the UPR and the inhibition of this pathway can inhibit growth in CARM1 expressing ovarian cancers.
- Jianhuang Lin
- , Heng Liu
- & Rugang Zhang
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Article
| Open AccessExtracellular matrix protein-1 secretory isoform promotes ovarian cancer through increasing alternative mRNA splicing and stemness
Extracellular matrix protein 1 (ECM1) has been associated with cancer but the underlying molecular mechanisms are not clear. Here, the authors show that while ECM1b isoform is a tumour suppressor, the secreted isoform ECM1a promotes tumourigenesis and chemoresistance through increasing stemness and alternative mRNA splicing in ovarian cancer.
- Huijing Yin
- , Jingshu Wang
- & Gong Yang
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Article
| Open AccessCo-evolution of matrisome and adaptive adhesion dynamics drives ovarian cancer chemoresistance
Platinum chemotherapy is standard of care in ovarian cancers but treatment resistance commonly develops. Here, the authors show that the extracellular microenvironment is modulated following chemotherapy and the changes in matrix proteins and stiffness alter the cell death response of tumour cells.
- Elina A. Pietilä
- , Jordi Gonzalez-Molina
- & Kaisa Lehti
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Article
| Open AccessEvolution of core archetypal phenotypes in progressive high grade serous ovarian cancer
High-grade serous ovarian cancer (HGSOC) is prone to developing resistance to treatment. Here, the authors use single-cell RNA-seq and an analysis of archetypes, and find that shifts in metabolism and proliferation are associated with the response to treatment and clonal heterogeneity in HGSOC.
- Aritro Nath
- , Patrick A. Cosgrove
- & Andrea H. Bild
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Article
| Open AccessMolecular and clinical determinants of response and resistance to rucaparib for recurrent ovarian cancer treatment in ARIEL2 (Parts 1 and 2)
The identification of biomarkers of response to PARP inhibitors can enable selection of appropriate ovarian cancer patients for treatment. In this study, the authors report clinical results and exploratory biomarker analyses from the ARIEL2 phase 2 clinical trial on the safety and efficacy of the PARP inhibitor rucaparib in patients with recurrent ovarian cancers
- Elizabeth M. Swisher
- , Tanya T. Kwan
- & Iain A. McNeish
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Article
| Open AccessPAX8 and MECOM are interaction partners driving ovarian cancer
Lineage-restricted transcription factor PAX8 is oncogenic in ovarian cancer cells. Here the authors show that PAX8 interacts and recruits a splice variant of the MECOM locus PRDM3 to control the gene expression module involved in adhesion and extracellular matrix, and consequently promotes ovarian tumorigenesis.
- Melusine Bleu
- , Fanny Mermet-Meillon
- & Giorgio Giacomo Galli
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Article
| Open AccessDiagnostic accuracy of cytology for the detection of endometrial cancer in urine and vaginal samples
Postmenopausal bleeding can be an indication of endometrial cancer. Here, the authors combine cytology of urine and vaginal samples from women with postmenopausal bleeding and demonstrate that they can accurately predict endometrial cancer with a sensitivity of 91.7% and specificity of 88.8%.
- Helena O’Flynn
- , Neil A. J. Ryan
- & Emma J. Crosbie
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Article
| Open AccessTransient commensal clonal interactions can drive tumor metastasis
Cooperative interactions among tumor cells may have important implications for metastasis. Here, the authors examined the spatio-temporal nature of interactions among clonal populations of ovarian carcinoma cells and found that transient interactions cells can promote metastases via commensal interactions.
- Suha Naffar-Abu Amara
- , Hendrik J. Kuiken
- & Joan S. Brugge