Ovarian Cancer Awareness Month

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.

Metabolic reprogramming is associated with cancer initiation, progression and resistance to therapy. Here, the authors show that metabolic reprogramming from glycolysis to fatty acid uptake and beta-oxidation is associated with cancer-cell platinum-based chemotherapy resistance.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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

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.

Mutations in the BARD1 gene have been identified as risk factors in breast and ovarian cancers. Here the authors reveal a synergetic effect between the occurance of two cis mutations in the BARD1 gene affecting the cellular DNA damage response and consequently tumorigenesis.

Breast cancer risk for BRCA1/BRCA2 mutation carriers varies depending on other genetic factors. Here, the authors perform a case-only genome-wide association study and highlight novel loci associated with breast cancer risk for BRCA1/BRCA2 mutation carriers.

Several strategies have been attempted to target immune suppressive populations in the tumor microenvironment. Here the authors show that folate receptor β-targeted CAR-T cells eliminate immunosuppressive tumor associated macrophages, promoting endogenous antitumor immune responses and adoptive T-cell therapy in pre-clinical models.

Ovarian cancer cells often metastasize to the peritoneal cavity, forming spheroid-like structures and promoting a highly immunosuppressive tumor microenvironment. Here, the authors show that the ubiquitin ligase UBR5 is required for ovarian cancer growth and metastasis, sustaining spheroid formation and the infiltration of immunosuppressive tumor associated macrophages.

Altered protein glycosylation is increasingly recognized as a hallmark of cancer. Here, the authors profile the glycoproteome of 119 high-grade serous ovarian carcinoma tissues, showing that glycosylation patterns correlate with tumor molecular subtypes and clinical outcomes.

The exclusion of T cells from solid tumours is a potentially important mechanism that regulates whether or not cancer patients respond well to checkpoint blocking immunotherapies. Here the authors identify immune phenotypes and mediators of T cell exclusion among ovarian cancer patient samples from the ICON7 phase III trial.

The folate receptor alpha (FRα) is overexpressed in the majority of high-grade serous ovarian cancers and has been proposed as a candidate vaccine antigen. Here the authors report the safety and immunogenicity of Th17-inducing dendritic cells pulsed with FRα-derived epitopes in an early phase I clinical trial with ovarian cancer patients.

The molecular classification of endometroid ovarian carcinomas (EnOC) has not been established, preventing the development of stratified therapeutic approaches. Here the authors characterise the molecular landscape of EnOC by whole exome sequencing, identifying clinically distinct disease subtypes.

Clinical proteomics critically depends on the ability to acquire highly reproducible data over an extended period of time. Here, the authors assess reproducibility over four months across different mass spectrometers and develop a computational approach to mitigate variation among instruments over time.

Genetic variation predisposes to disease via monogenic and polygenic risk variants. Here, the authors assess the interplay between these types of variation on disease penetrance in 80,928 individuals. In carriers of monogenic variants, they show that disease risk is a gradient influenced by polygenic background.

Advanced ovarian cancer usually spreads to the omentum. Here, the authors show that circulating intelectin-1 (ITLN1) has prognostic significance in patients with advanced ovarian cancer, and that mesothelial cell-derived ITLN1 in the omental tumor microenvironment suppresses ovarian cancer progression.

The bromodomain containing protein BRD9 has been reported to regulate chromatin remodeling and transcription. Here the authors reveal a role for BRD9 in homologous recombination by facilitating RAD51–RAD54 interaction.

p85β (PIK3R2), a regulatory subunit of PI3K, has oncogenic properties. Here the authors show that p85β promotes AXL protein stability, which in turn activates p110 to induce PDK1/SGK3 signaling, and therapeutically, p85β-expressing ovarian cancer cells are sensitive to AXL inhibition.

Macrophages can differentiate to perform homeostatic tissue-specific functions. Here the authors show that RXR signalling is critical for large peritoneal macrophage (LPM) expansion during neonatal life and LPM lipid metabolism and survival during adult homeostasis, and that ovarian cancer growth relies on RXR-dependent LPMs. 

Around half of the heritability underpinning familial high-grade serous ovarian carcinoma remains unidentified. Here, the authors show that extremely rare protein encoding loss-of-function variants, with a high degree of genetic heterogeneity, may account for some of this missing heritability.

A Phase I/II trial previously revealed variable anti-tumor efficacy of the PARP inhibitor niraparib in combination with the PD-1 inhibitor pembrolizumab in platinum-resistant ovarian cancer patients. Here, the authors perform an integrated genomic and immunomics analysis of tumor samples from the same patients and find potential predictive biomarkers of response to such combination therapy.

Patients with ovarium cancer frequently develop resistance to platinum chemotherapy and PARP inhibitors (PARPi). Here, the authors show that the combination of PARP and ATR inhibitors increases the therapeutic response in PARPi and platinum resistant ovarium cancer PDX models.

The relative contribution of fallopian tube (FT) or ovarian surface epithelium (OSE) to high-grade serous ovarian cancer (HG-SOC) development is unclear. Here, the authors establish organoid models from murine oviductal and OSE tissues that allow cancer modeling via CRISPR-Cas9 genome editing, and report a dual origin of murine HG-SOC.

Modern imaging techniques can detect cancer cells in the lymph nodes of cancer patients. In this study, the authors show that tumour related leukocytosis, a phenomenon where leukocytes are increased in number, can lead to the false positive detection of cancer cells in lymph nodes.

Acquired resistance limits the efficacy of PARP inhibitors (PARPi) in high grade serous ovarian cancer (HGSOC). Here, the authors show that inhibition of RNA polymerase I transcription using CX-5461 increases the therapeutic efficacy of PARPi and overcomes PARPi resistance in PDX models of HGSOC.

The mechanisms by which deubiquitinases modulate tumour progression are not fully understood. Here, the authors perform an RNAi screen and identify that the deubiquitinase OTUD5 suppresses cancer growth in a TRIM25 dependent manner, which in turn controls the expression of tumour suppressor protein, PML.

High-grade serous ovarian carcinoma is often associated with TP53 mutation and chromosomal instability (CIN). Here, the authors generate ex vivo cultures from biopsies and ascites of patients and perform characterization to evaluate CIN mechanisms and compare drug sensitivity with patient responses.

The role of non-coding somatic mutations in ovarian cancer is unclear. Here, the authors integrate genomic and epigenomic data from patient samples to show that these mutations frequently converge on the PAX8 transcriptional network.

Little is known about the genetics of sclerosing stromal tumor of the ovary, a rare type of sex cord-stromal tumor. Here, the authors use sequencing strategies to show that in a cohort of 26 tumor samples 65% carry a FHL2-GLI2 fusion gene and demonstrate in vitro that the fusion gene has oncogenic properties.

The clinical application of T cell bispecific antibodies (TCBs) is often limited by the lack of tumour-specific antigens. In this study, the authors present a strategy to increase TCB tumour-selectivity by adding an anti-CD3 moiety that can be specifically activated by tumor specific proteases in the tumor microenvironment.

Utilising identical genetic aberrations but targeting different cells, Zhang and colleagues seek to uncover how the cell of origin influences high-grade serous ovarian cancer biology, metastasis and response to treatment.

Tumor cell in the peritoneum are often exposed to shear forces generated by ascitic flow during metastasis. Here, the authors show that metastatic cancer stem cells tether more and roll slower than the non-metastatic counterparts, and that sialyl-Lewis^x -P-selectin axis mediates peritoneal metastasis.

Loss of PIK3R1 in ovarian cancer is a common event, which provides opportunities for therapeutic intervention. Here, the authors show that the STAT3 and AKT signaling pathways are activated upon PIK3R1 loss and that, in mice, inhibitors of these pathways could block tumorigenesis.

Cancer cells respond differently to inhibitors of Poly (ADP-ribose) polymerase. Here the authors reveal that ovarian cancer cells with higher cellular NADP+ levels are more sensitive to clinically relevant PARP1 inhibitors and show that NADP+ act as an endogenous inhibitor of PARP enzymes.

Epigenomic data on chromatin accessibility and transcription factor occupancy can reveal enhancer landscapes in cancer. Here, the authors develop a computational strategy called PSIONIC (patient-specific inference of networks informed by chromatin) to model the impact of enhancers on transcriptional programs in gynecologic and basal breast cancers.

Carcinosarcoma of the ovary or uterus comprises both carcinoma and sarcoma elements. Here, the authors perform a multi -omics study of the disease revealing therapeutic possibilities for this rare and aggressive disease.

High-grade serous ovarian cancers (HGSOCs) have defects in homologous recombination despite a lack of BRCA1/2 mutations. Here, the authors show that ZC3H18 positively regulates BRCA1 transcription and its loss causes BRCA1 promoter methylation and increased HR deficiency in HGSOCs.

Radiomics—the quantification of features within tumor images—has shown prognostic potential in cancer. Here, the authors use a machine learning approach to develop a radiomic-based small set of descriptors to predict ovarian cancer patient survival based on CT scans acquired pre-operatively in 364 patients.

Cancer cells employ a variety of ways to escape the immune system. Here, the authors show that ovarian cancer cells produce small extracellular vescicles containing arginase 1 that are taken up by dendritic cells in the draining lymph nodes, resulting in inhibition of antigen-specific T-cell proliferation.

Whether mucinous ovarian carcinoma (MOC) arises from cells at the ovary or from metastases from other primary sites is an unanswered question. Here, Cheasley et al perform a genetic analysis of the disease, showing that MOC arises at the ovary.

It is unclear whether fallopian tube epithelium or ovarian surface epithelium is the cell-of-origin of high grade serous ovarian carcinoma (HGSOC). Here the authors report a dualistic origin for HGSOC using genetically engineered mouse models and observe differential chemotherapy sensitivity depending on the cell-of-origin.

Ran, a nucleus-cytoplasm shuttle protein, is implicated in cancer development and survival. Here, the authors show that Ran binds RhoA to impair its degradation and allow its localisation to the plasma membrane of ovarian cancer cells for tumour invasion.