Biology subjects

Tang, N.

Publications and source records attributed to Tang, N..

35 records · Page 2Linked to original sources

bioRxiv2021

Bacterial-type plant ferroxidases tune local phosphate sensing in root development

Fluctuating bioavailability of inorganic phosphate (Pi), often caused by complex Pi-metal interactions, guide root tip growth and root system architecture for maximizing the foraged soil volume. Two interacting genes in Arabidopsis thaliana, PDR2 (P5-type ATPase) and LPR1 (multicopper oxidase), are central to external Pi monitoring by root tips, which is modified by iron (Fe) co-occurrence. Upon Pi deficiency, the PDR2-LPR1 module facilitates cell type-specific Fe accumulation and cell wall modifications in root meristems, inhibiting intercellular communication and thus root growth. LPR1 executes local Pi sensing, whereas PDR2 restricts LPR1 function. We show that native LPR1 displays specific ferroxidase activity and requires a conserved acidic triad motif for high-affinity Fe2+ binding and root growth inhibition under limiting Pi. Our data indicate that substrate availability tunes LPR1 function and implicate PDR2 in maintaining Fe homeostasis. LPR1 represents the prototype of an ancient ferroxidase family, which evolved very early upon bacterial colonization of land. During plant terrestrialization, horizontal gene transfer transmitted LPR1-type ferroxidase from soil bacteria to the common ancestor of Zygnematophyceae algae and embryophytes, a hypothesis supported by homology modeling, phylogenomics, and activity assays of bacterial LPR1-type multicopper oxidases.

plant biology↗

bioRxiv2021

Emerging SARS-CoV-2 variants reduce neutralization sensitivity to convalescent sera and monoclonal antibodies

SARS-CoV-2 Spike-specific antibodies contribute the majority of the neutralizing activity in most convalescent human sera. Two SARS-CoV-2 variants, N501Y.V1 (also known as B.1.1.7 lineage or VOC-202012/01) and N501Y.V2 (B.1.351 lineage), reported from the United Kingdom and South Africa, contain several mutations in the receptor binding domain of Spike and are of particular concern. To address the infectivity and neutralization escape phenotypes potentially caused by these mutations, we used SARS-CoV-2 pseudovirus system to compare the viral infectivity, as well as the neutralization activities of convalescent sera and monoclonal antibodies (mAbs) against SARS-CoV-2 variants. Our results showed that N501Y Variant 1 and Variant 2 increase viral infectivity compared to the reference strain (wild-type, WT) in vitro. At 8 months after symptom onset, 17 serum samples of 20 participants (85%) retaining titers of ID50 >40 against WT pseudovirus, whereas the NAb titers of 8 samples (40%) and 18 samples (90%) decreased below the threshold against N501Y.V1 and N501Y.V2, respectively. In addition, both N501Y Variant 1 and Variant 2 reduced neutralization sensitivity to most (6/8) mAbs tested, while N501Y.V2 even abrogated neutralizing activity of two mAbs. Taken together the results suggest that N501Y.V1 and N501Y.V2 reduce neutralization sensitivity to some convalescent sera and mAbs.

microbiology↗

bioRxiv2021

Deficiency of gluconeogenic enzyme PCK1 promotes non-alcoholic steatohepatitis progression by activation of PI3K/AKT/PDGF axis

Nonalcoholic steatohepatitis (NASH) is a chronic liver disease characterized by hepatic lipid accumulation, inflammation, and progressive fibrosis. We demonstrated that phosphoenolpyruvate carboxykinase 1 (PCK1) plays a central role in NASH progression. Mice with liver Pck1 deficiency fed a normal diet displayed hepatic lipid disorder and liver injury, whereas fibrosis and inflammation were aggravated in mice fed a NASH diet. Forced expression of PCK1 by adeno-associated virus in the liver ameliorated NASH in mice. PCK1 deficiency stimulated lipogenic gene expression and lipid synthesis. Moreover, loss of hepatic PCK1 activated the RhoA/PI3K/AKT pathway by increasing intracellular GTP levels, increasing secretion of platelet-derived growth factor-AA (PDGF-AA), and promoting hepatic stellate cell activation. Treatment with RhoA and AKT inhibitors or gene silencing of RhoA or AKT1 alleviated NASH progression in vivo. Hepatic PCK1 deficiency may be important in hepatic steatosis and fibrosis development through paracrine secretion of PDGF-AA, highlighting a therapeutic strategy for NASH.

molecular biology↗

bioRxiv2020

Identification of bis-benzylisoquinoline alkaloids as SARS-CoV-2 entry inhibitors from a library of natural products in vitro

Coronavirus disease 2019 (COVID-19) caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is a major public health issue. To screen for antiviral drugs for COVID-19 treatment, we constructed a SARS-CoV-2 spike (S) pseudovirus system using an HIV-1-based lentiviral vector with a luciferase reporter gene to screen 188 small potential antiviral compounds. Using this system, we identified nine compounds, specifically, bis-benzylisoquinoline alkaloids, that potently inhibited SARS-CoV-2 pseudovirus entry, with EC50 values of 0.1-10 M. Mechanistic studies showed that these compounds, reported as calcium channel blockers (CCBs), inhibited Ca2+-mediated membrane fusion and consequently suppressed coronavirus entry. These candidate drugs showed broad-spectrum efficacy against the entry of several coronavirus pseudotypes (SARS-CoV, MERS-CoV, SARS-CoV-2 [S-D614, S-G614, N501Y.V1 and N501Y.V2]) in different cell lines (293T, Calu-3, and A549). Antiviral tests using native SARS-CoV-2 in Vero E6 cells confirmed that four of the drugs (SC9/cepharanthine, SC161/hernandezine, SC171, and SC185/neferine) reduced cytopathic effect and supernatant viral RNA load. Among them, cepharanthine showed the strongest anti-SARS-CoV-2 activity. Collectively, this study offers new lead compounds for coronavirus antiviral drug discovery.

microbiology↗

bioRxiv2020

GSTZ1 sensitizes hepatocellular carcinoma cells to sorafenib-induced ferroptosis via inhibition of NRF2/GPX4 axis

Increasing evidence supports that ferroptosis plays an important role in tumor growth inhibition. Sorafenib, originally identified as an inhibitor of multiple oncogenic kinases, has been shown to induce ferroptosis in hepatocellular carcinoma (HCC). However, some hepatoma cell lines are less sensitive to sorafenib-induced ferroptotic cell death. Glutathione S-transferase zeta 1 (GSTZ1), an enzyme in the catabolism of phenylalanine, has been found to negatively regulate the master regulator of cellular redox homeostasis nuclear factor erythroid 2-related factor 2 (NRF2). This study aimed to investigate the role of GSTZ1 in sorafenib-induced ferroptosis in HCC cell lines and determine the involved molecular mechanisms. Mechanistically, GSTZ1 depletion enhanced the activation of the NRF2 pathway and increased the glutathione peroxidase 4 (GPX4) level, thereby suppressing sorafenib-induced ferroptosis. The combination of sorafenib and RSL3, a GPX4 inhibitor, significantly inhibited GSTZ1 deficient cell viability and promoted ferroptosis, accompanied with ectopic increases of iron and lipid peroxides. An in vivo experiment showed that the combination of sorafenib and RSL3 had a synergic therapeutic effect on HCC progression in Gstz1-/- mice. In conclusion, GSTZ1 was significantly downregulated in sorafenib resistant hepatoma cells. GSTZ1 enhanced sorafenib-induced ferroptosis by inhibiting the NRF2/GPX4 axis in HCC cells. GSTZ1 deficiency was resistant to sorafenib-induced ferroptosis and is, therefore, a potential therapeutic approach for treating HCC by synergizing sorafenib and RSL3 to induce ferroptosis.

cancer biology↗

bioRxiv2020

A key linear epitope for a potent neutralizing antibody to SARS-CoV-2 S-RBD

The spread of SARS-CoV-2 confers a serious threat to the public health without effective intervention strategies1-3. Its variant carrying mutated Spike (S) protein D614G (SD614G) has become the most prevalent form in the current global pandemic4,5. We have identified a large panel of potential neutralizing antibodies (NAbs) targeting the receptor-binding domain (RBD) of SARS-CoV-2 S6. Here, we focused on the top 20 potential NAbs for the mechanism study. Of them, the top 4 NAbs could individually neutralize both authentic SARS-CoV-2 and SD614G pseudovirus efficiently. Our epitope mapping revealed that 16/20 potent NAbs overlapped the same steric epitope. Excitingly, we found that one of these potent NAbs (58G6) exclusively bound to a linear epitope on S-RBD (termed as 58G6e), and the interaction of 58G6e and the recombinant ACE2 could be blocked by 58G6. We confirmed that 58G6e represented a key site of vulnerability on S-RBD and it could positively react with COVID-19 convalescent patients plasma. We are the first, as far as we know, to provide direct evidences of a linear epitope that can be recognized by a potent NAb against SARS-CoV-2 S-RBD. This study paves the way for the applications of these NAbs and the potential safe and effective vaccine design.

immunology↗

bioRxiv2020

A rapid and efficient screening system for neutralizing antibodies and its application for the discovery of potent neutralizing antibodies to SARS-CoV-2 S-RBD

Neutralizing antibodies (Abs) have been considered as promising therapeutics for the prevention and treatment of pathogens. After the outbreak of COVID-19, potent neutralizing Abs to SARS-CoV-2 were promptly developed, and a few of those neutralizing Abs are being tested in clinical studies. However, there were few methodologies detailly reported on how to rapidly and efficiently generate neutralizing Abs of interest. Here, we present a strategically optimized method for precisive screening of neutralizing monoclonal antibodies (mAbs), which enabled us to identify SARS-CoV-2 receptor-binding domain (RBD) specific Abs within 4 days, followed by another 2 days for neutralization activity evaluation. By applying the screening system, we obtained 198 Abs against the RBD of SARS-CoV-2. Excitingly, we found that approximately 50% (96/198) of them were candidate neutralizing Abs in a preliminary screening of SARS-CoV-2 pseudovirus and 20 of these 96 neutralizing Abs were confirmed with high potency. Furthermore, 2 mAbs with the highest neutralizing potency were identified to block authentic SARS-CoV-2 with the half-maximal inhibitory concentration (IC50) at concentrations of 9.88 ng/ml and 11.13 ng/ml. In this report, we demonstrated that the optimized neutralizing Abs screening system is useful for the rapid and efficient discovery of potent neutralizing Abs against SARS-CoV-2. Our study provides a methodology for the generation of preventive and therapeutic antibody drugs for emerging infectious diseases.

immunology↗

bioRxiv2020

Gluconeogenic Enzyme PCK1 Deficiency Is Critical for CHK2 O-GlcNAcylation and Hepatocellular Carcinoma Growth upon Glucose Deprivation

Elevated hexosamine-biosynthesis pathway (HBP) activity and O-GlcNAcylation are emerging hallmarks of hepatocellular carcinoma (HCC). Inhibiting O-GlcNAcylation could be a promising anti-cancer strategy. Here, we investigate this possibility and demonstrate that deficiency of phosphoenolpyruvate carboxykinase 1 (PCK1), a rate-limiting enzyme in gluconeogenesis, promotes O-GlcNAcylation and hepatoma cell proliferation under low-glucose conditions. PCK1 loss results in oxaloacetate accumulation and AMPK inactivation, promoting uridine diphosphate-N-acetylglucosamine (UDP-GlcNAc) synthesis and CHK2 threonine 378 O-GlcNAcylation and counteracting its ubiquitination and degradation. O-GlcNAcylation also promotes CHK2-dependent Rb phosphorylation and HCC cell proliferation. Therefore, blocking HBP-mediated O-GlcNAcylation suppresses tumor progression in liver-specific Pck1-knockout mice. We reveal a link between PCK1 depletion and hyper-O-GlcNAcylation that underlies HCC oncogenesis and suggest therapeutic targets for HCC that act by inhibiting O-GlcNAcylation.

cancer biology↗

bioRxiv2020

Dynamic multi-OMICs of glioblastoma reveal sensitivity to neddylation inhibition dependent on nuclear PTEN and DNA replication pathways

Withdrawal StatementThe authors have withdrawn their manuscript because the reported synergy of TOP2A inhibitors plus MLN4924 proved to be untrue (not reproducible). Therefore, the authors do not wish this work to be cited as reference for the project. If you have any questions, please contact the corresponding author (mberens@tgen.org).

cancer biology↗

bioRxiv2020

The D614G mutation of SARS-CoV-2 spike protein enhances viral infectivity and decreases neutralization sensitivity to individual convalescent sera

Coronavirus disease 2019 (COVID-19) is caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). The spike (S) protein that mediates SARS-CoV-2 entry into host cells is a major target for vaccines and therapeutics. Thus, insights into its sequence variations are key to understanding the infection and antigenicity of SARS-CoV-2. A dominant mutational variant at position 614 of the S protein (aspartate to glycine, D614G mutation) was observed in the SARS-CoV-2 genome sequence obtained from the Nextstrain database. Using a pseudovirus-based assay, we identified that S-D614 and S-G614 protein pseudotyped viruses share a common receptor, human angiotensin-converting enzyme 2 (ACE2), which could be blocked by recombinant ACE2 with the fused Fc region of human IgG1. However, S-D614 and S-G614 protein demonstrated functional differences. First, S-G614 protein could be cleaved by serine protease elastase-2 more efficiently. Second, S-G614 pseudovirus infected 293T-ACE2 cells significantly more efficiently than did the S-D614 pseudovirus, especially in the presence of elastase-2. Third, an elastase inhibitor approved for clinical use blocked elastase-enhanced S-G614 pseudovirus infection. Moreover, 93% (65/70) convalescent sera from patients with COVID-19 could neutralize both S-D614 and S-G614 pseudoviruses with comparable efficiencies, but about 7% (5/70) convalescent sera showed reduced neutralizing activity against the S-G614 pseudovirus. These findings have important implications for SARS-CoV-2 transmission and immune interventions.Competing Interest StatementThe authors have declared no competing interest.View Full Text

microbiology↗

bioRxiv2020

Transgenerational inheritance of abnormal spermatogenesis with Igf2/H19 epigenetic alteration in CD1 mouse induced by in utero arsenic exposure

Developmental exposure to environmental toxicants can induce transgenerational reproductive disease phenotypes through epigenetic mechanisms. However, little is known about the transgenerational effects of arsenic exposure. We hypothesize that prenatal arsenic exposure may result in impaired spermatogenesis in subsequent generations of male mice. To test our hypothesis, we treated pregnant CD-1 (F0) mice with drinking water containing sodium arsenite (85 ppm) from days 8 to 18 of gestation. Male offspring were bred with untreated female mice until the F3 generation was produced. Our results revealed that transient exposure of the F0 gestating female to arsenic can result in decreased sperm quality and histological abnormalities in testes of male offspring in the F1 and F3 generations. The overall methylation status of Igf2 DMR2 and H19 DMR was significantly lower in the arsenic-exposed group than that of the control group in both F1 and F3 generations. The relative mRNA expression levels of Igf2 and H19 in arsenic-exposed males were significantly higher than in the control males in both F1 and F3 generations. This study indicates that ancestral exposure to arsenic may result in transgenerational inheritance of an impaired spermatogenesis phenotyping involving both epigenetic alterations and the abnormal expression of Igf2 and H19.

pharmacology and toxicology↗

bioRxiv2020

A spatiotemporal translatome of mouse tissue development

The precise regulation of gene expression in mammalian tissues during development results in their functional specification. Although previous transcriptomic and proteomic analyses have provided great biological insights into tissue-specific gene expression and the physiological relevance of these tissues in development, our understanding of translational regulation in developing tissues is lacking. In this study, we performed a spatiotemporally resolved translatome analysis of six mouse tissues at the embryonic and adult stages to quantify the effects of translational regulation and identify new translational components. We quantified the spatial and temporal divergences of gene expression and detected specific changes in gene expression and pathways underlying these divergences. We further showed that dynamic translational control can be achieved by modulating the translational efficiency, which resulted in the enhancement of tissue specificity during development. We also discovered thousands of actively translated upstream open reading frames (ORFs) that exhibited spatiotemporal patterns and demonstrated their regulatory roles in translational regulation. Furthermore, we identified known and novel micropeptides encoded by small ORFs from long noncoding RNAs that are functionally relevant to tissue development. Our data and analyses facilitate a better understanding of the complexity of translational regulation across tissue and developmental spectra and serve as a useful resource of the mouse translatome.

bioinformatics↗

bioRxiv2020

O-GlcNAcylation of SAMHD1 Indicating a Link between Metabolic Reprogramming and Anti-HBV Immunity

Viruses hijack the host cell machinery to promote viral replication; however, the mechanism by which metabolic reprogramming regulates innate antiviral immunity in the host remains elusive. Herein, we found that Hepatitis B virus (HBV) infection upregulates glucose transporter 1expression, promotes hexosamine biosynthesis pathway (HBP) activity, and enhances O-linked {beta}-N-acetylglucosamine (O-GlcNAc) modification of downstream proteins. HBP-mediated O-GlcNAcylation positively regulates host antiviral response against HBV in vitro and in vivo. Mechanistically, O-GlcNAc transferase (OGT)-mediated O-GlcNAcylation of sterile alpha motif and histidine/aspartic acid domain-containing protein 1 (SAMHD1) on Ser93 stabilizes SAMHD1 and enhances its antiviral activity. In addition, O-GlcNAcylation of SAMHD1 promoted its antiviral activity against human immunodeficiency virus-1 in vitro. In conclusion, the results of our study reveal a link between HBP, O-GlcNAc modification, and innate antiviral immunity by targeting SAMHD1. Therefore, the results of this study demonstrate a strategy for the potential treatment of HBV infection by modulating HBP activity.

microbiology↗

bioRxiv2019

Benchmarking Computational Methods for Estimating the Pathogenicity of Wilson’s Disease Mutations

Genetic variations in the gene encoding the copper-transport protein ATP7B are the primary cause of Wilsons disease. Controversially, clinical prevalence seems much smaller than prevalence estimated by genetic screening tools, causing fear that many people are undiagnosed although early diagnosis and treatment is essential. To address this issue, we benchmarked 16 state-of-the-art computational disease-prediction methods against established data of missense ATP7B mutations. Our results show that the quality of the methods vary widely. We show the importance of optimizing the threshold of the methods used to distinguish pathogenic from non-pathogenic mutations against data of clinically confirmed pathogenic and non-pathogenic mutations. We find that most methods use thresholds that predict too many ATP7B mutations to be pathogenic. Thus, our findings explain the current controversy on Wilsons disease prevalence, because meta analysis and text search methods include many computational estimates that lead to higher disease prevalence than clinically observed. Since proteins differ widely, a one-size-fits-all threshold for all proteins cannot distinguish efficiently pathogenic and non-pathogenic mutations, as shown here. We also show that amino acid changes with small evolutionary substitution probability, mainly due to amino acid volume, are more associated with disease, implying a pathological effect on the conformational state of the protein, which could affect copper transport or ATP recognition and hydrolysis. These findings may be a first step towards a more quantitative genotype-phenotype relationship of Wilsons disease.

biochemistry↗

bioRxiv2019

STK11 is required for the normal program of ciliated cell differentiation in airways

The functional properties of mucosal surfaces are dependent on establishing the correct proportions of specialized epithelial cell types. Multiciliated cells (also known as ciliated cells) are evolutionarily conserved and functionally indispensable epithelial cells, as suggested by the link between ciliated cell dysfunction and chronic human disease. Ciliated cell differentiation is an ordered process that involves initial cell fate determination and multiciliogenesis. STK11, a serine/threonine kinase, has been reported to be down-regulated in human diseases associated with ciliopathies and functions as a tumor suppressor. Here, we show that STK11 is a physiological factor for the normal program of ciliated cell differentiation by phosphorylating MARK3, which directly suppresses ERK1/2 mediated pRB inactivation. Loss of Stk11 in airway progenitors impairs the differentiation of ciliated cells in both embryonic and adult airways. Our study establishes that STK11/MARK3/ERK1/2 signaling cascade is a key regulator to integrate ciliated cell fate commitment and the subsequent process of multiciliogenesis.

developmental biology↗

bioRxiv2019

Membrane dynamics of Notch-bound γ-secretase produces two distinct Notch conformations

Cleavage of Notch by the major intramembrane aspartyl protease complex {gamma}-secretase is a central event in cell regulation and is also important to Alzheimers disease, with more than 200 mutations in the catalytic subunit of {gamma}-secretase (PS1) causing severe early-onset forms of the disease. Recently, cryogenic electron microscopy (cryo-EM) has revealed the electron density of the protein-Notch complex in frozen solution, indicating major changes upon substrate binding and a possible helix unwinding to expose peptide bonds. In order understand the all-atom dynamics that cause this process, and to test the Notch binding in a membrane protein rather than solution, we developed an all-atom model of mature wild-type {gamma}-secretase bound to Notch in a complete membrane-water system and studied the system using three independent 500-nanosecond molecular dynamics simulations. Our ensembles are in essential agreement with known cryo-EM data. As in previous simulations we find unusual {beta}-strand transitions in exposed parts of PS1. We also observe the atomic helix motions that cause loss of helicity in bound Notch by direct comparison to corresponding 500 ns simulations of free Notch, in particular five residues to the N-terminal site of the primary cleavage site. Most importantly, we identify three conformation states, with two of them differing in the Notch-bound catalytic site. These dynamics produce a ping-pong relationship of positioning the S3 cleavage sites of Notch relative to the aspartates. These conformation states are not visible in the cryo-EM data; probably the density is an average snapshot of the two states. Our identified conformation states rationalize how Notch cleavage can be imprecise and yield multiple products. Our identified conformation states may aid efforts to develop conformation-selective drugs that target C99 and Notch cleavage differently.\n\nStatement of SignificanceThe atomic dynamics underlying cleavage of Notch by {gamma}-secretase in the membrane is of major biological importance. Electron microscopy has revealed the protein-Notch complex in frozen solution, showing major changes upon substrate binding and helix unwinding to expose peptide bonds, but does not explain why substrate cleavage is imprecise and produces several products. Our model of wild-type {gamma}-secretase bound to Notch in a complete membrane-water system equilibrated by 3 x 500 nanoseconds of molecular dynamics strongly complements the electron microscopy data: We identify the specific loop and helix motions that cause the {beta}-strand transitions in PS1 and the loss of helicity in specific residues of bound Notch. We identify different conformations of Notch, which importantly affect the S3 cleavage site; the open state may cause the imprecise cleavage with earlier release of products. Our identified states can aid development of conformation-selective drugs that target C99 and Notch cleavage differently.

biophysics↗

bioRxiv2017

Ponatinib shows potent antitumor activity in small cell carcinoma of the ovary hypercalcemic type (SCCOHT) through multi-kinase inhibition

Structured AbstractPurpose: Subunits of the SWI/SNF chromatin-remodeling complex are tumor suppressors inactivated in [~]20% of all cancers. Yet, few targeted treatments for SWI/SNF-mutant cancers exist. Small cell carcinoma of the ovary, hypercalcemic type (SCCOHT) is a rare, aggressive ovarian cancer in young women that is universally driven by loss of the SWI/SNF ATPase subunits, SMARCA4 and SMARCA2. Given poor two-year survival rates for these women, a great need exists for effective targeted therapies.\n\nExperimental Design: To identify underlying therapeutic vulnerabilities in SCCOHT, we conducted high-throughput siRNA and drug screens. Complementary proteomics approaches comprehensively profiled kinases inhibited by ponatinib. Ponatinib was tested for efficacy in two PDX models and one cell line xenograft model of SCCOHT.\n\nResults: FGFRs and PDGFRs were overlapping hits between screens and the receptor tyrosine kinase (RTK) family was enriched in the siRNA screen hits. Evaluation of eleven RTK inhibitors in three SCCOHT cell lines identified ponatinib, an inhibitor of multiple RTKs, as the most effective clinically approved agent. Proteomics approaches confirmed inhibition of known targets of ponatinib and more than 20 non-canonical ponatinib targets. Ponatinib also delayed tumor doubling time 4-fold in SCCOHT-1 xenografts and reducing final tumor volumes in two SCCOHT patient-derived xenograft (PDX) models by 58.6% and 42.5%.\n\nConclusion: Ponatinib is an effective agent for SCCOHT in both in vitro and in vivo preclinical models through its inhibition of multiple kinases. Clinical investigation of this FDA-approved oncology drug in SCCOHT is warranted.\n\nAdditional InformationThis work was supported by research funds from the Canadian Cancer Society Research Institute 34 (#703458, D.G.H.), the National Institutes of Health (R01 CA195670-01, B.E.W., D.G.H., and 35 J.M.T., and T32 HL007106-39 to E.M.C), the Terry Fox Research Institute Initiative New Frontiers Program in Cancer (#1021, D.G.H.), the British Columbia Cancer Foundation (D.G.H.), the VGH & UBC Foundation (D.G.H.), the Anne Rita Monahan Foundation (P.R.), the Marsha Rivkin Center for Ovarian Cancer Research (J.M.T.), the Ovarian Cancer Alliance of Arizona (J.M.T.), the Small Cell Ovarian Cancer Foundation (P.R., J.D.L., B.V., and J.M.T.), and philanthropic support to the TGen Foundation (J.M.T.).\n\nCOI disclosure statement: The authors declare no potential conflicts of interest.

cancer biology↗