RESUMO
Ovarian cancer (OC) manifests as a complex disease characterized by inter- and intra-patient heterogeneity. Despite enhanced biological and genetic insights, OC remains a recalcitrant malignancy with minimal survival improvement. Based on multi-site sampling and a multi-lineage patient-derived xenograft (PDX) establishment strategy, we present herein the establishment of a comprehensive PDX biobank from histologically and molecularly heterogeneous OC patients. Comprehensive profiling of matched PDX and patient samples demonstrates that PDXs closely recapitulate parental tumors. By leveraging multi-lineage models, we reveal that the previously reported genomic disparities of PDX could be mainly attributed to intra-patient spatial heterogeneity instead of substantial model-independent genomic evolution. Moreover, DNA damage response pathway inhibitor (DDRi) screening uncovers heterogeneous responses across models. Prolonged iterative drug exposure recapitulates acquired drug resistance in initially sensitive models. Meanwhile, interrogation of induced drug-resistant (IDR) models reveals that suppressed interferon (IFN) response and activated Wnt/ß-catenin signaling contribute to acquired DDRi drug resistance.
Assuntos
Neoplasias Ovarianas , Humanos , Feminino , Neoplasias Ovarianas/genética , Neoplasias Ovarianas/patologia , Neoplasias Ovarianas/metabolismo , Animais , Camundongos , Ensaios Antitumorais Modelo de Xenoenxerto , Via de Sinalização Wnt/genética , Resistencia a Medicamentos Antineoplásicos/genética , Genômica/métodos , Bancos de Espécimes Biológicos , Heterogeneidade Genética , Dano ao DNA/genética , Interferons/metabolismo , Interferons/genética , Linhagem da Célula/genéticaRESUMO
Cervical squamous cell carcinoma (CSCC) exhibits a limited response to immune-checkpoint blockade. Here we conducted a multiomic analysis encompassing single-cell RNA sequencing, spatial transcriptomics and spatial proteomics, combined with genetic and pharmacological perturbations to systematically develop a high-resolution and spatially resolved map of intratumoral expression heterogeneity in CSCC. Three tumor states (epithelial-cytokeratin, epithelial-immune (Epi-Imm) and epithelial senescence), recapitulating different stages of squamous differentiation, showed distinct tumor immune microenvironments. Bidirectional interactions between epithelial-cytokeratin malignant cells and immunosuppressive cancer-associated fibroblasts form an immune exclusionary microenvironment through transforming growth factor ß pathway signaling mediated by FABP5. In Epi-Imm tumors, malignant cells interact with natural killer and T cells through interferon signaling. Preliminary analysis of samples from a cervical cancer clinical trial ( NCT04516616 ) demonstrated neoadjuvant chemotherapy induces a state transition to Epi-Imm, which correlates with pathological complete remission following treatment with immune-checkpoint blockade. These findings deepen the understanding of cellular state diversity in CSCC.
Assuntos
Carcinoma de Células Escamosas , Neoplasias do Colo do Útero , Feminino , Humanos , Carcinoma de Células Escamosas/tratamento farmacológico , Carcinoma de Células Escamosas/genética , Neoplasias do Colo do Útero/genética , Inibidores de Checkpoint Imunológico , Relevância Clínica , Ecossistema , Multiômica , Queratinas/metabolismo , Queratinas/uso terapêutico , Microambiente Tumoral/genética , Proteínas de Ligação a Ácido Graxo/uso terapêuticoRESUMO
BACKGROUND: Mismatch repair deficiency (dMMR) is a well-recognized biomarker for response to immune checkpoint blockade (ICB). Strategies to convert MMR-proficient (pMMR) to dMMR phenotype with the goal of sensitizing tumors to ICB are highly sought. The combination of bromodomain containing 4 (BRD4) inhibition and ICB provides a promising antitumor effect. However, the mechanisms underlying remain unknown. Here, we identify that BRD4 inhibition induces a persistent dMMR phenotype in cancers. METHODS: We confirmed the correlation between BRD4 and mismatch repair (MMR) by the bioinformatic analysis on The Cancer Genome Atlas and Clinical Proteomic Tumor Analysis Consortium data, and the statistical analysis on immunohistochemistry (IHC) scores of ovarian cancer specimens. The MMR genes (MLH1,MSH2,MSH6,PMS2) were measured by quantitative reverse transcription PCR, western blot, and IHC. The MMR status was confirmed by whole exome sequencing, RNA sequencing, MMR assay and hypoxanthine-guanine phosphoribosyl transferase gene mutation assay. The BRD4i AZD5153 resistant models were induced both in vitro and in vivo. The transcriptional effects of BRD4 on MMR genes were investigated by chromatin immunoprecipitation among cell lines and data from the Cistrome Data Browser. The therapeutic response to ICB was testified in vivo. The tumor immune microenvironment markers, such as CD4, CD8, TIM-3, FOXP3, were measured by flow cytometry. RESULTS: We identified the positive correlation between BRD4 and MMR genes in transcriptional and translational aspects. Also, the inhibition of BRD4 transcriptionally reduced MMR genes expression, resulting in dMMR status and elevated mutation loads. Furthermore, prolonged exposure to AZD5153 promoted a persistent dMMR signature both in vitro and in vivo, enhancing tumor immunogenicity, and increased sensitivity to α-programmed death ligand-1 therapy despite the acquired drug resistance. CONCLUSIONS: We demonstrated that BRD4 inhibition suppressed expression of genes critical to MMR, dampened MMR, and increased dMMR mutation signatures both in vitro and in vivo, sensitizing pMMR tumors to ICB. Importantly, even in BRD4 inhibitors (BRD4i)-resistant tumor models, the effects of BRD4i on MMR function were maintained rendering tumors sensitive to ICB. Together, these data identified a strategy to induce dMMR in pMMR tumors and further, indicated that BRD4i sensitive and resistant tumors could benefit from immunotherapy.
Assuntos
Neoplasias Colorretais , Proteínas Nucleares , Humanos , Proteínas Nucleares/genética , Inibidores de Checkpoint Imunológico , Reparo de Erro de Pareamento de DNA/genética , Fatores de Transcrição/genética , Proteômica , Neoplasias Colorretais/patologia , Mutação , Microambiente Tumoral , Proteínas de Ciclo Celular/genéticaRESUMO
Cervical cancer (CC) that is caused by high-risk human papillomavirus (HPV) remains a significant public health problem worldwide. HPV integration sites can be silent or actively transcribed, leading to the production of viral-host fusion transcripts. Herein, we demonstrate that only productive HPV integration sites were nonrandomly distributed across both viral and host genomes, suggesting that productive integration sites are under selection and likely to contribute to CC pathophysiology. Furthermore, using large-scale, multi-omics (clinical, genomic, transcriptional, proteomic, phosphoproteomic, and single-cell) data, we demonstrate that tumors with productive HPV integration are associated with higher E6/E7 proteins and enhanced tumor aggressiveness and immunoevasion. Importantly, productive HPV integration increases from carcinoma in situ to advanced disease. This study improves our understanding of the functional consequences of HPV fusion transcripts on the biology and pathophysiology of HPV-driven CCs, suggesting that productive HPV integration should be evaluated as an indicator of high risk for progression to aggressive cancers.
RESUMO
Ovarian cancer (OC) ranks first among gynecologic malignancies in terms of mortality. The benefits of poly (ADP-ribose) polymerase (PARP) inhibitors appear to be limited to OC with BRCA mutations. Concurrent administration of WEE1 inhibitors (eg, adavosertib (Ada)) and PARP inhibitors (eg, olaparib (Ola)) effectively suppress ovarian tumor growth regardless of BRCA mutation status, but is poorly tolerated. Henceforth, we aimed to seek a strategy to reduce the toxic effects of this combination by taking advantage of the mesoporous polydopamine (MPDA) nanoparticles with good biocompatibility and high drug loading capacity. In this work, we designed a tumor-targeting peptide TMTP1 modified MPDA-based nano-drug delivery system (TPNPs) for targeted co-delivery of Ada and Ola to treat OC. Ada and Ola could be effectively loaded into MPDA nanoplatform and showed tumor microenvironment triggered release behavior. The nanoparticles induced more apoptosis in OC cells, and significantly enhanced the synergy of combination therapy with Ada plus Ola in murine OC models. Moreover, the precise drug delivery of TPNPs towards tumor cells significantly diminished the toxic side effects caused by concurrent administration of Ada and Ola. Co-delivery of WEE1 inhibitors and PARP inhibitors via TPNPs represents a promising approach for the treatment of OC. STATEMENT OF SIGNIFICANCE: Combination therapy of WEE1 inhibitors (eg, Ada) with PARP inhibitors (eg, Ola) effectively suppress ovarian tumor growth regardless of BRCA mutation status. However, poor tolerability limits its clinical application. To address this issue, we construct a tumor-targeting nano-drug delivery system (TPNP) for co-delivery of Ada and Ola. The nanoparticles specifically target ovarian cancer and effectively enhance the antitumor effect while minimizing undesired toxic side effects. As the first nanomedicine co-loaded with a WEE1 inhibitor and a PARP inhibitor, TPNP-Ada-Ola may provide a promising and generally applicable therapeutic strategy for ovarian cancer patients.
Assuntos
Nanopartículas , Neoplasias Ovarianas , Animais , Feminino , Humanos , Camundongos , Linhagem Celular Tumoral , Sistemas de Liberação de Fármacos por Nanopartículas/efeitos adversos , Neoplasias Ovarianas/patologia , Inibidores de Poli(ADP-Ribose) Polimerases/efeitos adversos , Inibidores de Poli(ADP-Ribose) Polimerases/farmacologia , Inibidores de Poli(ADP-Ribose) Polimerases/uso terapêutico , Microambiente TumoralRESUMO
Ovarian cancer (OC) remains a clinical challenge for its difficulty in early diagnosis and insensitivity to treatments. Gut microbiota modulate multiple carcinoma progression through immunoregulation. The relationship between OC and gut microbiota has not been fully characterized. We find that the feces of patients with OC demonstrate different characteristics from benign controls. After fecal microbiota transplantation (FMT) from patients with OC into OC-bearing mice, the tumor development accelerates. Further, an Akkermansia supplementation with FMT significantly suppresses OC progression in mice. RNA sequencing of tumors shows that T cell activation pathways are upregulated after Akkermansia supplementation with FMT. Moreover, acetate accumulation accompanies Akkermansia abundance elevation, which is associated with enhanced interferon γ (IFNγ) secretion of CD8+ T cells and also its tumor-killing property. This work highlights the importance of protective gut microbiome in immune surveillance of OC, which connects accumulation of acetate and the cytotoxic function of CD8+ T cells by increasing IFNγ secretion.
Assuntos
Transplante de Microbiota Fecal , Neoplasias Ovarianas , Camundongos , Animais , Feminino , Humanos , Akkermansia , Linfócitos T CD8-Positivos , Fezes , Neoplasias Ovarianas/terapia , Suplementos NutricionaisRESUMO
Tumor-infiltrating lymphocytes (TILs), especially CD8+ TILs, represent a favorable prognostic factor in high-grade serous ovarian cancer (HGSOC) and other tumor lineages. Here, we analyze the spatial heterogeneity of different TIL subtypes in HGSOC. We integrated RNA sequencing, whole-genome sequencing, bulk T cell receptor (TCR) sequencing, as well as single-cell RNA/TCR sequencing to investigate the characteristics and differential composition of TILs across different HGSOC sites. Two immune "cold" patterns in ovarian cancer are identified: (1) ovarian lesions with low infiltration of mainly dysfunctional T cells and immunosuppressive Treg cells and (2) omental lesions infiltrated with non-tumor-specific bystander cells. Exhausted CD8 T cells that are preferentially enriched in ovarian tumors exhibit evidence for expansion and cytotoxic activity. Inherent tumor immune microenvironment characteristics appear to be the main contributor to the spatial differences in TIL status. The landscape of spatial heterogeneity of TILs may inform potential strategies for therapeutic manipulation in HGSOC.
Assuntos
Cistos Ovarianos , Neoplasias Ovarianas , Humanos , Feminino , Neoplasias Ovarianas/genética , Neoplasias Ovarianas/patologia , Prognóstico , Multiômica , Receptores de Antígenos de Linfócitos T/genética , Microambiente Tumoral/genéticaRESUMO
Although resistance to poly(ADP-ribose) polymerase inhibitors (PARPi) has gradually become a major challenge in the maintenance therapy for high-grade serous ovarian carcinoma (HGSOC), there are no universal indicators for resistance monitoring in patients. A key resistance mechanism to PARPi is the restoration of homologous recombination repair (HRR), including BRCA reversion mutations and changes in DNA damage repair proteins. To explore mutation profiles associated with PARPi resistance, we undertook targeted 42-gene deep sequencing of circulating cell-free DNA (cfDNA) extracted from HGSOC patients pre- and post-treatment with olaparib maintenance therapy. We found that pathogenic germline mutations in the HRR pathway, including BRCA1/2, were strongly associated with improved clinical outcomes, and newly acquired MRE11A mutations significantly shortened the progression-free survival (PFS) of patients. Furthermore, dynamic fluctuations of somatic mutation sites in CHEK2:p.K373E and CHEK2:p.R406H can be used for evaluating the therapeutic efficacy of patients. MRE11A:p.K464R might be a vital driving factor of olaparib resistance, as patients with newly acquired MRE11A:p.K464R in post-treatment cfDNA had significantly shorter PFS than those without it. These findings provide potential noninvasive biomarkers for efficacy evaluation and resistance monitoring of olaparib treatment, and lay the foundation for developing combination treatment after olaparib resistance.
Assuntos
Ácidos Nucleicos Livres , Neoplasias Ovarianas , Resistencia a Medicamentos Antineoplásicos/genética , Feminino , Humanos , Mutação , Neoplasias Ovarianas/tratamento farmacológico , Neoplasias Ovarianas/genética , Neoplasias Ovarianas/patologia , Ftalazinas/farmacologia , Ftalazinas/uso terapêutico , Piperazinas , Inibidores de Poli(ADP-Ribose) Polimerases/farmacologia , Inibidores de Poli(ADP-Ribose) Polimerases/uso terapêuticoRESUMO
Targeting the G2/M checkpoint mediator WEE1 has been explored as a novel treatment strategy in ovarian cancer, but mechanisms underlying its efficacy and resistance remains to be understood. Here, it is demonstrated that the WEE1 inhibitor AZD1775 induces endoplasmic reticulum stress and activates the protein kinase RNA-like ER kinase (PERK) and inositol-required enzyme 1α (IRE1α) branches of the unfolded protein response (UPR) in TP53 mutant (mtTP53) ovarian cancer models. This is facilitated through NF-κB mediated senescence-associated secretory phenotype. Upon AZD1775 treatment, activated PERK promotes apoptotic signaling via C/EBP-homologous protein (CHOP), while IRE1α-induced splicing of XBP1 (XBP1s) maintains cell survival by repressing apoptosis. This leads to an encouraging synergistic antitumor effect of combining AZD1775 and an IRE1α inhibitor MKC8866 in multiple cell lines and preclinical models of ovarian cancers. Taken together, the data reveal an important dual role of the UPR signaling network in mtTP53 ovarian cancer models in response to AZD1775 and suggest that inhibition of the IRE1α-XBP1s pathway may enhance the efficacy of AZD1775 in the clinics.
Assuntos
Endorribonucleases , Neoplasias Ovarianas , Proteínas Serina-Treonina Quinases , Benzopiranos , Endorribonucleases/antagonistas & inibidores , Endorribonucleases/metabolismo , Feminino , Humanos , Inositol/metabolismo , Morfolinas , Neoplasias Ovarianas/tratamento farmacológico , Neoplasias Ovarianas/genética , Proteínas Serina-Treonina Quinases/antagonistas & inibidores , Proteínas Serina-Treonina Quinases/metabolismo , Pirazóis/farmacologia , Pirimidinonas/farmacologia , Proteína Supressora de Tumor p53/genética , Proteína Supressora de Tumor p53/metabolismo , Resposta a Proteínas não Dobradas/genética , Resposta a Proteínas não Dobradas/fisiologiaRESUMO
Targeted therapies represent attractive combination partners with immune checkpoint blockade (ICB) to increase the population of patients who benefit or to interdict the emergence of resistance. We demonstrate that targeting WEE1 up-regulates immune signaling through the double-stranded RNA (dsRNA) viral defense pathway with subsequent responsiveness to immune checkpoint blockade even in cGAS/STING-deficient tumors, which is a typical phenotype across multiple cancer types. WEE1 inhibition increases endogenous retroviral elements (ERVs) expression by relieving SETDB1/H3K9me3 repression through down-regulating FOXM1. ERVs trigger dsRNA stress and interferon response, increasing recruitment of anti-tumor T cells with concurrent PD-L1 elevation in multiple tumor models. Furthermore, combining WEE1 inhibition and PD-L1 blockade induced striking tumor regression in a CD8+ T cell-dependent manner. A WEE1 inhibition-induced viral defense signature provides a potentially informative biomarker for patient selection for combination therapy with WEE1 and ICB. WEE1 inhibition stimulates anti-tumor immunity and enhances sensitivity to ICB, providing a rationale for the combination of WEE1 inhibitors and ICB in clinical trials.
Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/farmacologia , Proteínas de Ciclo Celular/antagonistas & inibidores , Retrovirus Endógenos/genética , Neoplasias Experimentais/tratamento farmacológico , Proteínas Tirosina Quinases/antagonistas & inibidores , RNA de Cadeia Dupla/genética , Transdução de Sinais/efeitos dos fármacos , Células A549 , Animais , Linfócitos T CD8-Positivos/efeitos dos fármacos , Linfócitos T CD8-Positivos/imunologia , Linfócitos T CD8-Positivos/metabolismo , Proteínas de Ciclo Celular/genética , Proteínas de Ciclo Celular/metabolismo , Linhagem Celular Tumoral , Retrovirus Endógenos/metabolismo , Inibidores Enzimáticos/administração & dosagem , Inibidores Enzimáticos/farmacologia , Feminino , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Células HCT116 , Humanos , Inibidores de Checkpoint Imunológico/administração & dosagem , Inibidores de Checkpoint Imunológico/farmacologia , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos C57BL , Camundongos Endogâmicos NOD , Camundongos SCID , Neoplasias Experimentais/genética , Neoplasias Experimentais/imunologia , Proteínas Tirosina Quinases/genética , Proteínas Tirosina Quinases/metabolismo , Pirazóis/administração & dosagem , Pirazóis/farmacologia , Pirimidinonas/administração & dosagem , Pirimidinonas/farmacologia , RNA de Cadeia Dupla/metabolismo , Transdução de Sinais/genética , Carga Tumoral/efeitos dos fármacos , Carga Tumoral/genética , Carga Tumoral/imunologiaRESUMO
The CDK4/6 inhibitor, palbociclib has recently entered clinic-trial stage for breast cancer treatment. However, translating its efficacy to other solid tumors has been challenging, especially for aggressive solid tumors. We found that the effect of palbociclib as a single agent was limited due to primary and acquired resistance in multiple ovarian cancer (OC) models. Among these, patient-derived organoid and xenograft models are two most representative models of drug responsiveness in patients with OC. In preclinical models, this study demonstrated that activated MAPK/PI3K-AKT pathway and cell cycle-related proteins induced the resistance to palbociclib, which was overcome by the addition of the bromodomain protein 4 (BRD4) inhibitor AZD5153. Moreover, this study revealed that AZD5153 and palbociclib had a synergistic lethal effect on inducing the cell cycle arrest and increasing apoptosis, even in RB-deficient cell lines. Based on these results, it is anticipated that this class of drugs, including AZD5153, which inhibit the cell cycle-related protein and MAPK/PI3K-AKT pathway, will exhibit synergistic effects with palbociclib in OC.
Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Proteínas de Ciclo Celular/efeitos dos fármacos , Compostos Heterocíclicos com 2 Anéis/uso terapêutico , Quinases de Proteína Quinase Ativadas por Mitógeno/metabolismo , Neoplasias Ovarianas/tratamento farmacológico , Fosfatidilinositol 3-Quinases/metabolismo , Piperazinas/uso terapêutico , Proteínas Proto-Oncogênicas c-akt/metabolismo , Pirazóis/uso terapêutico , Piridazinas/uso terapêutico , Piridinas/uso terapêutico , Animais , Antineoplásicos , Protocolos de Quimioterapia Combinada Antineoplásica/farmacologia , Linhagem Celular Tumoral , Feminino , Compostos Heterocíclicos com 2 Anéis/farmacologia , Humanos , Camundongos , Piperazinas/farmacologia , Pirazóis/farmacologia , Piridazinas/farmacologia , Piridinas/farmacologia , Ensaios Antitumorais Modelo de XenoenxertoRESUMO
The vaginal microbiota is closely related to HPV infection and cervical cancer (CC), but its relationship with platinum-based chemotherapy responsiveness is unknown. The study aimed to investigate the vaginal microbiota diversity of women with locally advanced cervical cancer (LACC) and compare the differences between responders and nonresponders. We characterized the 16S rRNA gene sequencing of vaginal microbiome of 66 vaginal samples, including 26 LACC patients before neoadjuvant chemotherapy and 40 healthy controls. Compared with the healthy controls, alpha diversity was significantly increased in CC patients (p <0.05) with more unconventionality bacterial colonization. Beta diversity also significantly differed between cervical cancer patients and controls (p <0.01). Within the CC patients, alpha diversity in vaginal samples was significantly higher in the nonresponders versus the responders (p <0.01), and the Ace index and Chao index were negatively correlated with mass reduction (p <0.001). Moreover, the Bacteroides genus enriched in the nonresponders had a ROC-plot AUC value reaching 0.84. The study suggests the vaginal microbiota in LACC patients is associated with platinum-based chemotherapy responsiveness. Alpha diversity and Bacteroides abundance have the potential of identifying platinum-resistant patients at an early time. These findings provide a basis for further research on the relationship between vaginal microbiome and chemotherapy effect in LACC.
Assuntos
Microbiota , Neoplasias do Colo do Útero , Feminino , Humanos , Microbiota/genética , Terapia Neoadjuvante , RNA Ribossômico 16S/genética , Neoplasias do Colo do Útero/tratamento farmacológico , Neoplasias do Colo do Útero/microbiologia , Vagina/microbiologiaRESUMO
Ongoing pandemic and potential resurgence of Coronavirus disease 2019 (COVID-19) has prompted urgent efforts to investigate the immunological memory of convalescent patients, especially in patients with active cancers. Here we performed single-cell RNA sequencing in peripheral blood samples of 3 healthy donors (HDs), 4 COVID-19 patients (Covs) and 4 COVID-19 patients with active gynecological tumor (TCs) pre- and post- anti-tumor treatment. All Covs patients had recovered from their acute infection. Interestingly, the molecular features of PBMCs in TCs are similar to that in Covs, suggesting that convalescent COVID-19 with gynecologic tumors do not have major immunological changes and may be protected against reinfection similar to COVID-19 patients without tumors. Moreover, the chemotherapy given to these patients mainly caused neutropenia, while having little effect on the proportion and functional phenotype of T and B cells, and T cell clonal expansion. Notably, anti-PD-L1 treatment massively increased cytotoxic scores of NK cells, and T cells, and facilitated clonal expansion of T cells in these patients. It is likely that T cells could protect patients from SARS-CoV-2 virus reinfection and anti-PD-L1 treatment can enhance the anti-viral activity of the T cells.
Assuntos
COVID-19/complicações , Neoplasias dos Genitais Femininos/complicações , Neoplasias dos Genitais Femininos/terapia , Inibidores de Checkpoint Imunológico/uso terapêutico , Imunoterapia , Anticorpos Antivirais/imunologia , Linfócitos B/efeitos dos fármacos , Linfócitos B/imunologia , COVID-19/imunologia , COVID-19/prevenção & controle , Feminino , Neoplasias dos Genitais Femininos/imunologia , Humanos , Inibidores de Checkpoint Imunológico/farmacologia , SARS-CoV-2/efeitos dos fármacos , SARS-CoV-2/imunologia , Análise de Célula Única , Linfócitos T/efeitos dos fármacos , Linfócitos T/imunologiaRESUMO
BACKGROUND: To date, there is no approved blood-based biomarker for breast cancer detection. Herein, we aimed to assess semaphorin 4C (SEMA4C), a pivotal protein involved in breast cancer progression, as a serum diagnostic biomarker. METHODS: We included 6,213 consecutive inpatients from Tongji Hospital, Qilu Hospital, and Hubei Cancer Hospital. Training cohort and two validation cohorts were introduced for diagnostic exploration and validation. A pan-cancer cohort was used to independently explore the diagnostic potential of SEMA4C among solid tumors. Breast cancer patients who underwent mass excision prior to modified radical mastectomy were also analyzed. We hypothesized that increased pre-treatment serum SEMA4C levels, measured using optimized in-house enzyme-linked immunosorbent assay kits, could detect breast cancer. The endpoints were diagnostic performance, including area under the receiver operating characteristic curve (AUC), sensitivity, and specificity. Post-surgery pathological diagnosis was the reference standard and breast cancer staging followed the TNM classification. There was no restriction on disease stage for eligibilities. RESULTS: We included 2667 inpatients with breast lesions, 2378 patients with other solid tumors, and 1168 healthy participants. Specifically, 118 patients with breast cancer were diagnosed with stage 0 (5.71%), 620 with stage I (30.00%), 966 with stage II (46.73%), 217 with stage III (10.50%), and 8 with stage IV (0.39%). Patients with breast cancer had significantly higher serum SEMA4C levels than benign breast tumor patients and normal controls (P < 0.001). Elevated serum SEMA4C levels had AUC of 0.920 (95% confidence interval [CI]: 0.900-0.941) and 0.932 (95%CI: 0.911-0.953) for breast cancer detection in the two validation cohorts. The AUCs for detecting early-stage breast cancer (n = 366) and ductal carcinoma in situ (n = 85) were 0.931 (95%CI: 0.916-0.946) and 0.879 (95%CI: 0.832-0.925), respectively. Serum SEMA4C levels significantly decreased after surgery, and the reduction was more striking after modified radical mastectomy, compared with mass excision (P < 0.001). The positive rate of enhanced serum SEMA4C levels was 84.77% for breast cancer and below 20.75% for the other 14 solid tumors. CONCLUSIONS: Serum SEMA4C demonstrated promising potential as a candidate biomarker for breast cancer diagnosis. However, validation in prospective settings and by other study groups is warranted.
Assuntos
Neoplasias da Mama , Semaforinas , Biomarcadores Tumorais , Neoplasias da Mama/diagnóstico , Feminino , Humanos , Mastectomia , Estudos Prospectivos , Estudos RetrospectivosRESUMO
BACKGROUND: Gynecologic cancers seriously threaten women's life and health. This study aims to assess the long-term trends of mortality from the three major gynecologic cancers in China and to examine the age-, period-, and cohort-specific effects behind them during the period 1990 to 2019. METHODS: The mortality data of cervical, ovarian, and uterine cancer in China were obtained from the Global Burden of Disease Study 2019 and were analyzed with the age-period-cohort framework. RESULTS: It was found that the net drift for cervical cancer mortality was -0.19% (95% CI, -0.46% to 0.08%) per year, for ovarian cancer was 0.76% (95% CI, 0.57% to 0.95%) per year, and for uterine cancer was -3.09% (95% CI, -3.44% to -2.76%) per year from 1990 to 2019. During this period, while cervical cancer remained the most common cause of death among gynecologic cancers among Chinese women, ovarian cancer replaced uterine cancer as the second leading cause of death in gynecologic cancers after about 2005. Significant age, cohort, and period effects were found for the mortality trends of all three major gynecologic cancers. CONCLUSIONS: The secular trends of mortality from the three major gynecologic cancers in China and their underlying age, period, and cohort effects are likely to reflect the progress of diagnosis and treatment, rapid socio-economic transitions, and the accompanying lifestyle and behavior changes. More priorities of further epidemiology studies and efforts on the prevention and control should be given to three major gynecologic cancers.
Assuntos
Neoplasias Ovarianas/mortalidade , Neoplasias do Colo do Útero/mortalidade , Neoplasias Uterinas/mortalidade , Adulto , Fatores Etários , Idoso , Povo Asiático/estatística & dados numéricos , China/epidemiologia , Efeito de Coortes , Feminino , História do Século XX , História do Século XXI , Humanos , Pessoa de Meia-Idade , Mortalidade/história , Mortalidade/tendências , Neoplasias Ovarianas/história , Neoplasias do Colo do Útero/história , Neoplasias Uterinas/história , Adulto JovemRESUMO
WEE1 plays an important role in the regulation of cell cycle G2/M checkpoints and DNA damage response (DDR). Inhibition of WEE1 can increase the instability of the genome and have anti-tumor effects in some solid tumors. However, it has certain limitations for multiple cancer cells from different lineages. Therefore, we consider the use of synthetic lethal interactions to enhance the therapeutic effect. Our experiments proved that WEE1 inhibitor (WEE1i) can activate the ataxia telangiectasia and RAD3-related (ATR) pathway and that blockage of ATR dramatically sensitized the WEE1i-induced cell death. The tumor-selective synthetic lethality between bioavailable WEE1 and ATR inhibitors led to tumor remission in vivo. Mechanistically, the combination promoted the accumulation of cytosolic double-strand DNA, which subsequently activated the stimulator of the interferon gene (STING) pathway and induced the production of type I interferon and CD8+ T cells, thereby inducing anti-tumor immunity. Furthermore, our study found that immune checkpoint programmed death-ligand 1 is upregulated by the combination therapy, and blocking PD-L1 further enhances the effect of the combination therapy. In summary, as an immunomodulator, the combination of WEE1i with ATR inhibitor (ATRi) and immune checkpoint blockers provides a potential new approach for cancer treatment.
Assuntos
Proteínas Mutadas de Ataxia Telangiectasia/antagonistas & inibidores , Antígeno B7-H1/antagonistas & inibidores , Proteínas de Ciclo Celular/antagonistas & inibidores , Neoplasias Colorretais/tratamento farmacológico , Terapia de Alvo Molecular/métodos , Neoplasias Ovarianas/tratamento farmacológico , Inibidores de Proteínas Quinases/uso terapêutico , Proteínas Tirosina Quinases/antagonistas & inibidores , Animais , Proteínas Mutadas de Ataxia Telangiectasia/metabolismo , Antígeno B7-H1/metabolismo , Linfócitos T CD8-Positivos , Morte Celular , Linhagem Celular Tumoral , DNA/metabolismo , Dano ao DNA , DNA de Neoplasias/biossíntese , Modelos Animais de Doenças , Sinergismo Farmacológico , Feminino , Pontos de Checagem da Fase G2 do Ciclo Celular/efeitos dos fármacos , Instabilidade Genômica , Humanos , Imunidade , Imunoterapia/métodos , Indóis/uso terapêutico , Interferon Tipo I/biossíntese , Pontos de Checagem da Fase M do Ciclo Celular/efeitos dos fármacos , Proteínas de Membrana/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Morfolinas/uso terapêutico , Pirazóis/uso terapêutico , Pirimidinas/uso terapêutico , Pirimidinonas/uso terapêutico , Sulfonamidas/uso terapêutico , Microambiente Tumoral/imunologia , Ensaio Tumoral de Célula-Tronco , Regulação para CimaRESUMO
The outbreak of coronavirus disease 2019 (COVID-19) is a global health emergency. Various omics results have been reported for COVID-19, but the molecular hallmarks of COVID-19, especially in those patients without comorbidities, have not been fully investigated. Here we collect blood samples from 231 COVID-19 patients, prefiltered to exclude those with selected comorbidities, yet with symptoms ranging from asymptomatic to critically ill. Using integrative analysis of genomic, transcriptomic, proteomic, metabolomic and lipidomic profiles, we report a trans-omics landscape for COVID-19. Our analyses find neutrophils heterogeneity between asymptomatic and critically ill patients. Meanwhile, neutrophils over-activation, arginine depletion and tryptophan metabolites accumulation correlate with T cell dysfunction in critical patients. Our multi-omics data and characterization of peripheral blood from COVID-19 patients may thus help provide clues regarding pathophysiology of and potential therapeutic strategies for COVID-19.
Assuntos
COVID-19/genética , COVID-19/metabolismo , Estado Terminal , Genômica/métodos , Humanos , Lipidômica/métodos , Metabolômica/métodos , Neutrófilos/metabolismo , Transcriptoma/genéticaRESUMO
The characteristics of COVID-19 patients with persistent SARS-CoV-2 infection are not yet well described. Here, we compare the clinical and molecular features of patients with long duration of viral shedding (LDs) with those from patients with short duration patients (SDs), and healthy donors (HDs). We find that several cytokines and chemokines, such as interleukin (IL)-2, tumor necrosis factor (TNF) and lymphotoxin α (LT-α) are present at lower levels in LDs than SDs. Single-cell RNA sequencing shows that natural killer (NK) cells and CD14+ monocytes are reduced, while regulatory T cells are increased in LDs; moreover, T and NK cells in LDs are less activated than in SDs. Importantly, most cells in LDs show reduced expression of ribosomal protein (RP) genes and related pathways, with this inversed correlation between RP levels and infection duration further validated in 103 independent patients. Our results thus indicate that immunosuppression and low RP expression may be related to the persistence of the viral infection in COVID-19 patients.
Assuntos
COVID-19/imunologia , SARS-CoV-2/patogenicidade , Linfócitos B/metabolismo , Linfócitos B/patologia , COVID-19/virologia , Citocinas/sangue , Perfilação da Expressão Gênica , Humanos , Células Matadoras Naturais/metabolismo , Células Matadoras Naturais/patologia , Leucócitos Mononucleares/patologia , Ativação Linfocitária/genética , Subpopulações de Linfócitos/metabolismo , Subpopulações de Linfócitos/patologia , Proteínas Ribossômicas/genética , SARS-CoV-2/isolamento & purificação , Transdução de Sinais/genética , Linfócitos T/metabolismo , Linfócitos T/patologia , Eliminação de Partículas ViraisRESUMO
Vulvovaginal atrophy (VVA) is a common menopause-related symptom affecting more than 50% of midlife and older women and cancer patients whose ovarian function are lost or damaged. Regardless of estrogen deficiency, whether other factors such as the gut microbiota play role in VVA have not been thoroughly investigated. To this end, we performed ovariectomy on 12-weeks' old mice and follow-up at 4 weeks after ovariectomy, and observed atrophied vagina and an altered gut microbiota in ovariectomized mice.. We further performed fecal microbiota transplantation with feces from another cohort of ovary-intact fecund female mice to the ovariectomized ones, and found that the vaginal epithelial atrophy was significantly alleviated as well as the gut microbiota was pointedly changed. All these results suggest that ovarian activity has some influence on the gut microbiota, and the latter from the ovary-intact female mice can somehow make the vagina of mice deficient in ovarian function healthier maybe by up-expressing ESR1 in vaginal cells and enhancing regeneration in vagina. This kind of association between gut microbiota and vaginal health need further exploration such that it may provide an alternative treatment by modulating gut microbiota in patients suffering from VVA but may be reluctant to hormone therapy.
Assuntos
Transplante de Microbiota Fecal , Ovariectomia/efeitos adversos , Vagina/patologia , Animais , Atrofia , Feminino , Microbioma Gastrointestinal/genética , Microbioma Gastrointestinal/fisiologia , Camundongos , Camundongos Endogâmicos C57BL , RNA Ribossômico 16S/genéticaRESUMO
Mutant KRAS tumors are associated with poor outcomes, at least in part, due to decreased therapeutic sensitivity. Here, we show that KRAS mutations are associated with resistance to monotherapy and combination therapy with PARP inhibitors (PARPi) and immune checkpoint blockade with anti-PD-L1 antibodies. In mutant KRAS tumors, inhibition of KRAS signaling with MEK inhibitors (MEKi) triggered and amplified PARPi-induced DNA damage, cytosolic double-stranded DNA accumulation, STING pathway activation, and CD8+ T-cell recruitment. Moreover, MEKi decreased myeloid-derived suppressor cell infiltration, in part, by inhibiting IL6 and GMCSF production. Importantly, addition of MEKi to PARPi and anti-PD-L1 resulted in marked tumor inhibition in immunocompetent mutant KRAS tumor models. This study provides the underlying mechanistic data to support evaluation of PARPi, MEKi, and anti-PD-L1 combination in clinical trials of mutant KRAS tumors. SIGNIFICANCE: This study provides key insights into the potential for using MEKi combined with PARPi and anti-PD-L1 for the treatment of all mutant KRAS tumors. GRAPHICAL ABSTRACT: http://cancerres.aacrjournals.org/content/canres/81/10/2714/F1.large.jpg.