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1.
J Hematol Oncol ; 15(1): 45, 2022 04 27.
Artigo em Inglês | MEDLINE | ID: mdl-35477416

RESUMO

Targeting nucleotide metabolism can not only inhibit tumor initiation and progression but also exert serious side effects. With in-depth studies of nucleotide metabolism, our understanding of nucleotide metabolism in tumors has revealed their non-proliferative effects on immune escape, indicating the potential effectiveness of nucleotide antimetabolites for enhancing immunotherapy. A growing body of evidence now supports the concept that targeting nucleotide metabolism can increase the antitumor immune response by (1) activating host immune systems via maintaining the concentrations of several important metabolites, such as adenosine and ATP, (2) promoting immunogenicity caused by increased mutability and genomic instability by disrupting the purine and pyrimidine pool, and (3) releasing nucleoside analogs via microbes to regulate immunity. Therapeutic approaches targeting nucleotide metabolism combined with immunotherapy have achieved exciting success in preclinical animal models. Here, we review how dysregulated nucleotide metabolism can promote tumor growth and interact with the host immune system, and we provide future insights into targeting nucleotide metabolism for immunotherapeutic treatment of various malignancies.


Assuntos
Imunoterapia , Neoplasias , Animais , Humanos , Fatores Imunológicos/uso terapêutico , Neoplasias/tratamento farmacológico , Nucleotídeos/uso terapêutico
2.
Cell Rep ; 39(4): 110732, 2022 04 26.
Artigo em Inglês | MEDLINE | ID: mdl-35476980

RESUMO

RNA polymerase II (Pol II)-mediated transcription in metazoans requires precise regulation. RNA Pol II-associated protein 2 (RPAP2) was previously identified to transport Pol II from cytoplasm to nucleus and dephosphorylates Pol II C-terminal domain (CTD). Here, we show that RPAP2 binds hypo-/hyper-phosphorylated Pol II with undetectable phosphatase activity. The structure of RPAP2-Pol II shows mutually exclusive assembly of RPAP2-Pol II and pre-initiation complex (PIC) due to three steric clashes. RPAP2 prevents and disrupts Pol II-TFIIF interaction and impairs in vitro transcription initiation, suggesting a function in inhibiting PIC assembly. Loss of RPAP2 in cells leads to global accumulation of TFIIF and Pol II at promoters, indicating a critical role of RPAP2 in inhibiting PIC assembly independent of its putative phosphatase activity. Our study indicates that RPAP2 functions as a gatekeeper to inhibit PIC assembly and transcription initiation and suggests a transcription checkpoint.


Assuntos
Núcleo Celular , RNA Polimerase II , Núcleo Celular/metabolismo , Monoéster Fosfórico Hidrolases/metabolismo , Regiões Promotoras Genéticas/genética , RNA Polimerase II/metabolismo
3.
Cancer Biol Med ; 2022 Apr 05.
Artigo em Inglês | MEDLINE | ID: mdl-35380032

RESUMO

Breast cancer is the most common malignant tumor in Chinese women, and its incidence is increasing. Regular screening is an effective method for early tumor detection and improving patient prognosis. In this review, we analyze the epidemiological changes and risk factors associated with breast cancer in China and describe the establishment of a screening strategy suitable for Chinese women. Chinese patients with breast cancer tend to be younger than Western patients and to have denser breasts. Therefore, the age of initial screening in Chinese women should be earlier, and the importance of screening with a combination of ultrasound and mammography is stressed. Moreover, Chinese patients with breast cancers have several ancestry-specific genetic features, and aiding in the determination of genetic screening strategies for identifying high-risk populations. On the basis of current studies, we summarize the development of risk-stratified breast cancer screening guidelines for Chinese women and describe the significant improvement in the prognosis of patients with breast cancer in China.

4.
Cell Rep ; 38(10): 110492, 2022 03 08.
Artigo em Inglês | MEDLINE | ID: mdl-35263601

RESUMO

Immune checkpoint inhibitor (ICI) therapy is generating remarkable responses in individuals with cancer, but only a small portion of individuals with breast cancer respond well. Here we report that tumor-derived Jagged1 is a key regulator of the tumor immune microenvironment. Jagged1 promotes tumorigenesis in multiple spontaneous mammary tumor models. Through Jagged1-induced Notch activation, tumor cells increase expression and secretion of multiple cytokines to help recruit macrophages into the tumor microenvironment. Educated macrophages crosstalk with tumor-infiltrating T cells to inhibit T cell proliferation and tumoricidal activity. In individuals with triple-negative breast cancer, a high expression level of Jagged1 correlates with increased macrophage infiltration and decreased T cell activity. Co-administration of an ICI PD-1 antibody with a Notch inhibitor significantly inhibits tumor growth in breast cancer models. Our findings establish a distinct signaling cascade by which Jagged1 promotes adaptive immune evasion of tumor cells and provide several possible therapeutic targets.


Assuntos
Evasão da Resposta Imune , Neoplasias de Mama Triplo Negativas , Humanos , Macrófagos/metabolismo , Transdução de Sinais , Neoplasias de Mama Triplo Negativas/metabolismo , Microambiente Tumoral
5.
Mol Cancer ; 21(1): 84, 2022 03 25.
Artigo em Inglês | MEDLINE | ID: mdl-35337339

RESUMO

BACKGROUND: Immune checkpoint inhibitors had a great effect in triple-negative breast cancer (TNBC); however, they benefited only a subset of patients, underscoring the need to co-target alternative pathways and select optimal patients. Herein, we investigated patient subpopulations more likely to benefit from immunotherapy and inform more effective combination regimens for TNBC patients. METHODS: We conducted exploratory analyses in the FUSCC cohort to characterize a novel patient selection method and actionable targets for TNBC immunotherapy. We investigated this in vivo and launched a phase 2 trial to assess the clinical value of such criteria and combination regimen. Furthermore, we collected clinicopathological and next-generation sequencing data to illustrate biomarkers for patient outcomes. RESULTS: CD8-positivity could identify an immunomodulatory subpopulation of TNBCs with higher possibilities to benefit from immunotherapy, and angiogenesis was an actionable target to facilitate checkpoint blockade. We conducted the phase II FUTURE-C-Plus trial to assess the feasibility of combining famitinib (an angiogenesis inhibitor), camrelizumab (a PD-1 monoclonal antibody) and chemotherapy in advanced immunomodulatory TNBC patients. Within 48 enrolled patients, the objective response rate was 81.3% (95% CI, 70.2-92.3), and the median progression-free survival was 13.6 months (95% CI, 8.4-18.8). No treatment-related deaths were reported. Patients with CD8- and/or PD-L1- positive tumors benefit more from this regimen. PKD1 somatic mutation indicates worse progression-free and overall survival. CONCLUSION: This study confirms the efficacy and safety of the triplet regimen in immunomodulatory TNBC and reveals the potential of combining CD8, PD-L1 and somatic mutations to guide clinical decision-making and treatments. TRIAL REGISTRATION: ClinicalTrials.gov: NCT04129996 . Registered 11 October 2019.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica , Neoplasias de Mama Triplo Negativas , Inibidores da Angiogênese/uso terapêutico , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Antígeno B7-H1/genética , Biomarcadores Tumorais/metabolismo , Humanos , Neovascularização Patológica/tratamento farmacológico , Receptor de Morte Celular Programada 1/genética , Neoplasias de Mama Triplo Negativas/tratamento farmacológico , Neoplasias de Mama Triplo Negativas/genética , Neoplasias de Mama Triplo Negativas/patologia
6.
Nat Commun ; 13(1): 1478, 2022 03 18.
Artigo em Inglês | MEDLINE | ID: mdl-35304469

RESUMO

Mis-regulated RNA modifications promote the processing and translation of oncogenic mRNAs to facilitate cancer progression, while the molecular mechanisms remain unclear. Here we reveal that tRNA m7G methyltransferase complex proteins METTL1 and WDR4 are significantly up-regulated in esophageal squamous cell carcinoma (ESCC) tissues and associated with poor ESCC prognosis. In addition, METTL1 and WDR4 promote ESCC progression via the tRNA m7G methyltransferase activity in vitro and in vivo. Mechanistically, METTL1 or WDR4 knockdown leads to decreased expression of m7G-modified tRNAs and reduces the translation of a subset of oncogenic transcripts enriched in RPTOR/ULK1/autophagy pathway. Furthermore, ESCC models using Mettl1 conditional knockout and knockin mice uncover the essential function of METTL1 in promoting ESCC tumorigenesis in vivo. Our study demonstrates the important oncogenic function of mis-regulated tRNA m7G modification in ESCC, and suggest that targeting METTL1 and its downstream signaling axis could be a promising therapeutic target for ESCC treatment.


Assuntos
Neoplasias Esofágicas , Carcinoma de Células Escamosas do Esôfago , Animais , Autofagia/genética , Carcinogênese/genética , Linhagem Celular Tumoral , Proliferação de Células/genética , Neoplasias Esofágicas/genética , Carcinoma de Células Escamosas do Esôfago/genética , Carcinoma de Células Escamosas do Esôfago/metabolismo , Regulação Neoplásica da Expressão Gênica , Guanosina/análogos & derivados , Metiltransferases/genética , Metiltransferases/metabolismo , Camundongos , RNA de Transferência/genética
7.
Breast Cancer Res Treat ; 193(2): 319-330, 2022 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-35334008

RESUMO

PURPOSE: Triple-negative breast cancer (TNBC) is a highly heterogeneous disease. Patients with early-stage TNBCs have distinct likelihood of distant recurrence. This study aimed to develop a prognostic signature of early-stage TNBC patients to improve risk stratification. METHODS: Using RNA-sequencing data, we analyzed 189 pathologically confirmed pT1-2N0M0 TNBC patients and identified 21 mRNAs that were highly expressed in tumor and related to relapse-free survival. All-subset regression program was used for constructing a 7-mRNA signature in the training set (n = 159); the accuracy and prognostic value were then validated using an independent validation set (n = 158). RESULTS: Here, we profiled the transcriptome data from 189 early-stage TNBC patients along with 50 paired normal tissues. Early-stage TNBCs mainly consisted of basal-like immune-suppressed subtype and had higher homologous recombination deficiency scores. We developed a prognostic signature including seven mRNAs (ACAN, KRT5, TMEM101, LCA5, RPP40, LAGE3, CDKL2). In both the training (n = 159) and validation set (n = 158), this signature could identify patients with relatively high recurrence risks and served as an independent prognostic factor. Time-dependent receiver operating curve showed that the signature had better prognostic value than traditional clinicopathological features in both sets. Functionally, we showed that TMEM101 promoted cell proliferation and migration in vitro, which represented a potential therapeutic target. CONCLUSIONS: Our 7-mRNA signature could accurately predict recurrence risks of early-stage TNBCs. This model may facilitate personalized therapy decision-making for early-stage TNBCs individuals.


Assuntos
Neoplasias da Mama , Neoplasias de Mama Triplo Negativas , Biomarcadores Tumorais/genética , Feminino , Perfilação da Expressão Gênica , Humanos , Recidiva Local de Neoplasia/genética , Recidiva Local de Neoplasia/patologia , Prognóstico , RNA Mensageiro/genética , Ribonuclease P/genética , Transcriptoma , Neoplasias de Mama Triplo Negativas/tratamento farmacológico , Neoplasias de Mama Triplo Negativas/terapia
8.
Cell Rep ; 38(9): 110460, 2022 03 01.
Artigo em Inglês | MEDLINE | ID: mdl-35235781

RESUMO

We report a comprehensive proteomic study of a 90-case cohort of paired samples of triple-negative breast cancer (TNBC) in quantification, phosphorylation, and DNA-binding capacity. Four integrative subtypes (iP-1-4) are stratified on the basis of global proteome and phosphoproteome, each of which exhibits distinct molecular and pathway features. Scaffold and co-expression network analyses of three proteomic datasets, integrated with those from genome and transcriptome of the same cohort, reveal key pathways and master regulators that, characteristic of TNBC subtypes, play important regulatory roles within and between scaffold sub-structures and co-expression communities. We find that NAE1 is a potential drug target for subtype iP-1, and a series of key molecules in fatty acid metabolism, such as AKT1/FASN, are plausible targets for subtype iP-2. Libraries of proteins, pathways and networks of TNBC provide a valuable molecular infrastructure for further clinical exploration and in-depth studies of the molecular mechanisms of the disease.


Assuntos
Neoplasias de Mama Triplo Negativas , Genoma , Humanos , Proteoma/genética , Proteômica , Transcriptoma , Neoplasias de Mama Triplo Negativas/genética , Neoplasias de Mama Triplo Negativas/metabolismo
9.
Cell Metab ; 34(4): 581-594.e8, 2022 Apr 05.
Artigo em Inglês | MEDLINE | ID: mdl-35278352

RESUMO

Immunotherapy has achieved limited success in patients with triple-negative breast cancer (TNBC), an aggressive disease with a poor prognosis. Commensal microbiota have been proven to colonize the mammary gland, but whether and how they modulate the tumor microenvironment remains elusive. We performed a multiomics analysis of a cohort of patients with TNBC (n = 360) and found genera under Clostridiales, and the related metabolite trimethylamine N-oxide (TMAO) was more abundant in tumors with an activated immune microenvironment. Patients with higher plasma TMAO achieved better responses to immunotherapy. Mechanistically, TMAO induced pyroptosis in tumor cells by activating the endoplasmic reticulum stress kinase PERK and thus enhanced CD8+ T cell-mediated antitumor immunity in TNBC in vivo. Collectively, our findings offer new insights into microbiota-metabolite-immune crosstalk and indicate that microbial metabolites, such as TMAO or its precursor choline, may represent a novel therapeutic strategy to promote the efficacy of immunotherapy in TNBC.


Assuntos
Microbiota , Neoplasias de Mama Triplo Negativas , Colina/metabolismo , Humanos , Metilaminas/metabolismo , Microambiente Tumoral
10.
Mol Ther Oncolytics ; 24: 624-635, 2022 Mar 17.
Artigo em Inglês | MEDLINE | ID: mdl-35284626

RESUMO

Triple-negative breast cancer (TNBC) is an aggressive type of breast cancer. High fibrosis, marked by increased collagen fibers, is widespread in TNBC and correlated with tumor progression. However, the molecular features of fibrosis and why it results in a poor prognosis remain poorly understood. Based on multiomics datasets of TNBC, we evaluated the pathological fibrosis grade of 344 samples for further analysis. Genomic, transcriptomic, and immune changes were analyzed among different subgroups of fibrosis. High fibrosis was an independent adverse prognosis predictor and had interactions with low stromal tumor-infiltrating lymphocytes. Genomic analysis identified copy number gains of 6p22.2-6p22.1 (TRIM27) and 20q13.33 (CDH4) as genomic hallmarks of tumors with high fibrosis. Transcriptome analysis revealed the transforming growth factor-beta pathway and hypoxia pathway were key pro-oncogenic pathways in tumors with high fibrosis. Moreover, we systematically evaluate the relationship between fibrosis and different kinds of immune and stromal cells. Tumors with high fibrosis were characterized by an immunosuppressive tumor microenvironment with limited immune cell infiltration and increased fibroblasts. This study proposes new insight into the genomic and transcriptomic alterations potentially driving fibrosis. Moreover, fibrosis is related to an immunosuppressive tumor microenvironment that contributes to the poor prognosis.

11.
Clin Cancer Res ; 2022 Mar 03.
Artigo em Inglês | MEDLINE | ID: mdl-35247906

RESUMO

PURPOSE: Camrelizumab, a monoclonal antibody against PD-1, plus nab-paclitaxel exhibited promising antitumor activity in refractory metastatic immunomodulatory triple-negative breast cancer (TNBC). Famitinib is a tyrosine kinase inhibitor targeting VEGFR2, PDGFR and c-kit. We aimed to assess the efficacy and safety of a novel combination of famitinib, camrelizumab and nab-paclitaxel in advanced immunomodulatory TNBC. PATIENTS AND METHODS: This open-label, single-arm, phase II study enrolled patients with previously untreated, advanced, immunomodulatory TNBC (CD8 immunohistochemical staining {greater than or equal to} 10%). Eligible patients received 20 mg of oral famitinib on days 1-28, 200 mg of intravenous camrelizumab on days 1 and 15, and intravenous nab-paclitaxel 100 mg/m2 on days 1, 8 and 15 in 4-week cycles. The primary endpoint was objective response rate (ORR), as assessed by investigators per RECIST v1.1. Key secondary endpoints were progression-free survival (PFS), overall survival (OS), duration of response (DOR), safety and exploratory biomarkers. RESULTS: Forty-eight patients were enrolled and treated. Median follow-up was 17.0 months (range, 8.7-24.3). Confirmed ORR was 81.3% (95% CI, 70.2-92.3), with 5 complete and 34 partial responses. Median PFS was 13.6 months (95% CI, 8.4-18.8), and median DOR was 14.9 months (95% CI, NE-NE). Median OS was not reached. No treatment-related deaths were reported. Among 30 patients with immunohistochemistry, 13 (43.3%) were PD-L1-positive, and PD-L1 was associated with favorable response. PKD1 and KAT6A somatic mutations were associated with therapy response. CONCLUSIONS: The triplet regimen was efficacious and well tolerated in previously untreated, advanced, immunomodulatoryTNBC. The randomized controlled FUTURE-SUPER trial is underway to validate our findings.

12.
Cell Res ; 32(5): 477-490, 2022 May.
Artigo em Inglês | MEDLINE | ID: mdl-35105939

RESUMO

Metabolic reprogramming is a hallmark of cancer. However, systematic characterizations of metabolites in triple-negative breast cancer (TNBC) are still lacking. Our study profiled the polar metabolome and lipidome in 330 TNBC samples and 149 paired normal breast tissues to construct a large metabolomic atlas of TNBC. Combining with previously established transcriptomic and genomic data of the same cohort, we conducted a comprehensive analysis linking TNBC metabolome to genomics. Our study classified TNBCs into three distinct metabolomic subgroups: C1, characterized by the enrichment of ceramides and fatty acids; C2, featured with the upregulation of metabolites related to oxidation reaction and glycosyl transfer; and C3, having the lowest level of metabolic dysregulation. Based on this newly developed metabolomic dataset, we refined previous TNBC transcriptomic subtypes and identified some crucial subtype-specific metabolites as potential therapeutic targets. The transcriptomic luminal androgen receptor (LAR) subtype overlapped with metabolomic C1 subtype. Experiments on patient-derived organoid and xenograft models indicate that targeting sphingosine-1-phosphate (S1P), an intermediate of the ceramide pathway, is a promising therapy for LAR tumors. Moreover, the transcriptomic basal-like immune-suppressed (BLIS) subtype contained two prognostic metabolomic subgroups (C2 and C3), which could be distinguished through machine-learning methods. We show that N-acetyl-aspartyl-glutamate is a crucial tumor-promoting metabolite and potential therapeutic target for high-risk BLIS tumors. Together, our study reveals the clinical significance of TNBC metabolomics, which can not only optimize the transcriptomic subtyping system, but also suggest novel therapeutic targets. This metabolomic dataset can serve as a useful public resource to promote precision treatment of TNBC.


Assuntos
Neoplasias de Mama Triplo Negativas , Biomarcadores Tumorais/genética , Humanos , Metabolômica , Medicina de Precisão , Transcriptoma , Neoplasias de Mama Triplo Negativas/genética , Neoplasias de Mama Triplo Negativas/patologia
13.
Nat Cancer ; 3(1): 60-74, 2022 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-35121988

RESUMO

Despite increased overall survival rates, curative options for metastatic breast cancer remain limited. We have previously shown that metadherin (MTDH) is frequently overexpressed in poor prognosis breast cancer, where it promotes metastasis and therapy resistance through its interaction with staphylococcal nuclease domain-containing 1 (SND1). Through genetic and pharmacological targeting of the MTDH-SND1 interaction, we reveal a key role for this complex in suppressing antitumor T cell responses in breast cancer. The MTDH-SND1 complex reduces tumor antigen presentation and inhibits T cell infiltration and activation by binding to and destabilizing Tap1/2 messenger RNAs, which encode key components of the antigen-presentation machinery. Following small-molecule compound C26-A6 treatment to disrupt the MTDH-SND1 complex, we showed enhanced immune surveillance and sensitivity to anti-programmed cell death protein 1 therapy in preclinical models of metastatic breast cancer, in support of this combination therapy as a viable approach to increase immune-checkpoint blockade therapy responses in metastatic breast cancer.


Assuntos
Neoplasias da Mama , Apresentação do Antígeno , Neoplasias da Mama/tratamento farmacológico , Endonucleases/metabolismo , Feminino , Humanos , Proteínas de Membrana/metabolismo , Nuclease do Micrococo/metabolismo , Proteínas Nucleares/genética , Proteínas de Ligação a RNA/metabolismo , Fatores de Transcrição/metabolismo
14.
Nat Cancer ; 3(1): 43-59, 2022 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-35121987

RESUMO

Metastatic breast cancer is a leading health burden worldwide. Previous studies have shown that metadherin (MTDH) promotes breast cancer initiation, metastasis and therapy resistance; however, the therapeutic potential of targeting MTDH remains largely unexplored. Here, we used genetically modified mice and demonstrate that genetic ablation of Mtdh inhibits breast cancer development through disrupting the interaction with staphylococcal nuclease domain-containing 1 (SND1), which is required to sustain breast cancer progression in established tumors. We performed a small-molecule compound screening to identify a class of specific inhibitors that disrupts the protein-protein interaction (PPI) between MTDH and SND1 and show that our lead candidate compounds C26-A2 and C26-A6 suppressed tumor growth and metastasis and enhanced chemotherapy sensitivity in preclinical models of triple-negative breast cancer (TNBC). Our results demonstrate a significant therapeutic potential in targeting the MTDH-SND1 complex and identify a new class of therapeutic agents for metastatic breast cancer.


Assuntos
Endonucleases/metabolismo , Proteínas de Membrana/metabolismo , Nuclease do Micrococo , Proteínas de Ligação a RNA/metabolismo , Neoplasias de Mama Triplo Negativas , Animais , Moléculas de Adesão Celular/genética , Humanos , Proteínas de Membrana/genética , Camundongos , Proteínas de Ligação a RNA/genética , Fatores de Transcrição
15.
Genes Dis ; 9(1): 268-274, 2022 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-35005123

RESUMO

Ribosome RNA (rRNA) accounts for more than 80% of the cell's total RNA, while the physiological functions of rRNA modifications are poorly understood. Mutations of 18S rRNA m6A methyltransferase METTL5 cause intellectual disability, microcephaly, and facial dysmorphisms in patients, however, little is known about the underlying mechanisms. In this study, we identified METTL5 protein complex and revealed that METTL5 mainly interacts with RNA binding proteins and ribosome proteins. Functionally, we found that Mettl5 knockout in mESCs leads to the abnormal craniofacial and nervous development. Moreover, using Mettl5 knockout mouse model, we further demonstrated that Mettl5 knockout mice exhibit intellectual disability, recapitulating the human phenotype. Mechanistically, we found that Mettl5 maintains brain function and intelligence by regulating the myelination process. Our study uncovered the causal correlation between mis-regulated 18S rRNA m6A modification and neural function defects, supporting the important physiological functions of rRNA modifications in human diseases.

16.
J Immunother Cancer ; 9(10)2021 10.
Artigo em Inglês | MEDLINE | ID: mdl-34615706

RESUMO

BACKGROUND: Triple-negative breast cancers (TNBCs), especially those non-immune-inflamed tumors, have a poor prognosis and limited therapies. Human leukocyte antigen (HLA)-I not only contributes to antitumor immune response and the phenotype of the tumor microenvironment, but also is a negative predictor of outcomes after immunotherapy. However, the importance of HLA functional status in TNBCs remains poorly understood. METHODS: Using the largest original multiomics datasets on TNBCs, we systematically characterized the HLA-Ⅰ status of TNBCs from the perspective of HLA-Ⅰ homogeneity and loss of heterozygosity (LOH). The prognostic significance of HLA-I status was measured. To explain the potential mechanism of prognostic value in HLA-Ⅰ status, the mutational signature, copy number alteration, neoantigen and intratumoral heterogeneity were measured. Furthermore, the correlation between HLA-Ⅰ functional status and the tumor immune microenvironment was analyzed. RESULTS: LOH and homogeneity in HLA-I accounted for 18% and 21% of TNBCs, respectively. HLA-I LOH instead of HLA-I homogeneity was an independent prognostic biomarker in TNBCs. In particular, for patients with non-immune-inflamed tumors, HLA-I LOH indicated a worse prognosis than HLA-I non-LOH. Furthermore, integrated genomic and transcriptomic analysis showed that HLA-I LOH was accompanied by upregulated scores of mutational signature 3 and homologous recombination deficiency scores, which implied the failure of DNA double-strand break repair. Moreover, HLA-I LOH had higher mutation and neoantigen loads and more subclones than HLA-I non-LOH. These results indicated that although HLA-I LOH tumors with failure of DNA double-strand break repair were prone to produce neoantigens, their limited capacity for antigen presentation finally contributed to poor immune selection pressure. CONCLUSION: Our study illustrates the genomic landscape of HLA-I functional status and stresses the prognostic significance of HLA-I LOH in TNBCs. For "cold" tumors in TNBCs, HLA-I LOH indicated a worse prognosis than HLA-I non-LOH.


Assuntos
Antígenos HLA/genética , Perda de Heterozigosidade/genética , Neoplasias de Mama Triplo Negativas/genética , Feminino , Humanos , Prognóstico , Análise de Sobrevida , Neoplasias de Mama Triplo Negativas/mortalidade
17.
Mol Ther Nucleic Acids ; 26: 333-346, 2021 Dec 03.
Artigo em Inglês | MEDLINE | ID: mdl-34513313

RESUMO

Esophageal cancer is a lethal malignancy with a high mortality rate, while the molecular mechanisms underlying esophageal cancer pathogenesis are still poorly understood. Here, we found that the N6-methyladenosine (m6A) methyltransferase-like 3 (METTL3) is significantly upregulated in esophageal squamous cell carcinoma (ESCC) and associated with poor patient prognosis. Depletion of METTL3 results in decreased ESCC growth and progression in vitro and in vivo. We further established ESCC initiation and progression models using Mettl3 conditional knockout mouse and revealed that 3METTL3-mediated m6A modification promotes ESCC initiation and progression in vivo. Moreover, using METTL3 overexpression ESCC cell model and Mettl3 conditional knockin mouse model, we demonstrated the critical function of METTL3 in promoting ESCC tumorigenesis in vitro and in vivo. Mechanistically, METTL3-catalyzed m6A modification promotes NOTCH1 expression and the activation of the Notch signaling pathway. Forced activation of Notch signaling pathway successfully rescues the growth, migration, and invasion capacities of METTL3-depleted ESCC cells. Our data uncovered important mechanistical insights underlying ESCC tumorigenesis and provided molecular basis for the development of novel strategies for ESCC diagnosis and treatment.

18.
Cancer Res ; 81(21): 5491-5505, 2021 11 01.
Artigo em Inglês | MEDLINE | ID: mdl-34408002

RESUMO

Genomic alterations are crucial for the development and progression of human cancers. Copy-number gains found in genes encoding metabolic enzymes may induce triple-negative breast cancer (TNBC) adaptation. However, little is known about how metabolic enzymes regulate TNBC metastasis. Using our previously constructed multiomic profiling of a TNBC cohort, we identified decaprenyl diphosphate synthase subunit 1 (PDSS1) as an essential gene for TNBC metastasis. PDSS1 expression was significantly upregulated in TNBC tissues compared with adjacent normal tissues and was positively associated with poor survival among patients with TNBC. PDSS1 knockdown inhibited TNBC cell migration, invasion, and distant metastasis. Mechanistically, PDSS1, but not a catalytically inactive mutant, positively regulated the cellular level of coenzyme Q10 (CoQ10) and intracellular calcium levels, thereby inducing CAMK2A phosphorylation, which is essential for STAT3 phosphorylation in the cytoplasm. Phosphorylated STAT3 entered the nucleus, promoting oncogenic STAT3 signaling and TNBC metastasis. STAT3 phosphorylation inhibitors (e.g., Stattic) effectively blocked PDSS1-induced cell migration and invasion in vitro and tumor metastasis in vivo. Taken together, our study highlights the importance of targeting the previously uncharacterized PDSS1/CAMK2A/STAT3 oncogenic signaling axis, expanding the repertoire of precision medicine in TNBC. SIGNIFICANCE: A novel metabolic gene PDSS1 is highly expressed in triple-negative breast cancer tissues and contributes to metastasis, serving as a potential therapeutic target for combating metastatic disease.


Assuntos
Alquil e Aril Transferases/metabolismo , Biomarcadores Tumorais/metabolismo , Proteína Quinase Tipo 2 Dependente de Cálcio-Calmodulina/metabolismo , Regulação Neoplásica da Expressão Gênica , Neoplasias Pulmonares/secundário , Fator de Transcrição STAT3/metabolismo , Neoplasias de Mama Triplo Negativas/patologia , Alquil e Aril Transferases/genética , Animais , Apoptose , Biomarcadores Tumorais/genética , Proteína Quinase Tipo 2 Dependente de Cálcio-Calmodulina/genética , Movimento Celular , Proliferação de Células , Feminino , Humanos , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/metabolismo , Camundongos , Camundongos Endogâmicos NOD , Camundongos SCID , Invasividade Neoplásica , Prognóstico , Fator de Transcrição STAT3/genética , Taxa de Sobrevida , Neoplasias de Mama Triplo Negativas/genética , Neoplasias de Mama Triplo Negativas/metabolismo , Células Tumorais Cultivadas , Ensaios Antitumorais Modelo de Xenoenxerto
19.
Signal Transduct Target Ther ; 6(1): 312, 2021 08 20.
Artigo em Inglês | MEDLINE | ID: mdl-34417437

RESUMO

Immunotherapies play critical roles in cancer treatment. However, given that only a few patients respond to immune checkpoint blockades and other immunotherapeutic strategies, more novel technologies are needed to decipher the complicated interplay between tumor cells and the components of the tumor immune microenvironment (TIME). Tumor immunomics refers to the integrated study of the TIME using immunogenomics, immunoproteomics, immune-bioinformatics, and other multi-omics data reflecting the immune states of tumors, which has relied on the rapid development of next-generation sequencing. High-throughput genomic and transcriptomic data may be utilized for calculating the abundance of immune cells and predicting tumor antigens, referring to immunogenomics. However, as bulk sequencing represents the average characteristics of a heterogeneous cell population, it fails to distinguish distinct cell subtypes. Single-cell-based technologies enable better dissection of the TIME through precise immune cell subpopulation and spatial architecture investigations. In addition, radiomics and digital pathology-based deep learning models largely contribute to research on cancer immunity. These artificial intelligence technologies have performed well in predicting response to immunotherapy, with profound significance in cancer therapy. In this review, we briefly summarize conventional and state-of-the-art technologies in the field of immunogenomics, single-cell and artificial intelligence, and present prospects for future research.


Assuntos
Antígenos de Neoplasias/genética , Genoma Humano/imunologia , Neoplasias/imunologia , Microambiente Tumoral/imunologia , Inteligência Artificial , Biomarcadores Tumorais/imunologia , Linhagem da Célula , Humanos , Imunidade Inata/genética , Imunogenética/tendências , Imunoterapia , Neoplasias/genética , Neoplasias/terapia , Proteoma/imunologia , Análise de Célula Única , Transcriptoma/imunologia
20.
J Immunother Cancer ; 9(7)2021 07.
Artigo em Inglês | MEDLINE | ID: mdl-34321275

RESUMO

BACKGROUND: Triple-negative breast cancer (TNBC) is the most aggressive subtype of breast cancer and lacks definite treatment targets. Tumor immune microenvironment (TIME) heterogeneity has a profound impact on the immunotherapy response. Tumors with non-inflamed TIME derive limited benefit from immunotherapy. However, what drives the formation of the non-inflamed TIME in TNBC remains unclear. METHODS: Using our multiomics database of TNBC, we conducted an analysis to explore the key genomic events driving the formation of the non-inflamed TIME in TNBC. In vitro and in vivo studies further revealed potential mechanisms and the efficacy of combination treatment with immunotherapy. RESULTS: With transcriptomic and genomic data, we systematically analyzed the TIME of TNBC and revealed that the classical basal-like subtype of TNBC consisted of two distinct microenvironment phenotypes, defined as the 'inflamed' and 'non-inflamed' subtypes. We performed further screening and demonstrated that MYC amplification and overexpression led to low immune infiltration and cytolytic activity in TIME. Mechanistically, MYC bound to DNMT1 promoter and activated DNMT1 transcription in TNBC cells, thus suppressing the Cyclic GMP-AMP synthase (cGAS)-STING pathway via an epigenetic regulatory way. In MYC-overexpressing TNBC, decitabine, an Food and Drug Administration (FDA)-approved DNA methyltransferase inhibitor, converted tumors from non-inflamed to inflamed tumors by enhancing T cell infiltration. Furthermore, the combination of decitabine with programmed cell death protein 1 (PD-1) inhibitor reversed T cell exhaustion and improved T cell function in mouse models, which elicited potent antitumor activity in MYC-overexpressing TNBC. CONCLUSIONS: Our work elucidates that the classic oncogene MYC induces immune evasion by repressing innate immunity. Furthermore, we provide a rationale for combining DNA methyltransferase inhibition with immunotherapy for the treatment of MYC-overexpressing TNBC.


Assuntos
DNA (Citosina-5-)-Metiltransferase 1/imunologia , Imunidade Inata/imunologia , Proteínas de Membrana/imunologia , Proteínas Proto-Oncogênicas c-myc/imunologia , Neoplasias de Mama Triplo Negativas/imunologia , Animais , DNA (Citosina-5-)-Metiltransferase 1/genética , DNA (Citosina-5-)-Metiltransferase 1/metabolismo , Feminino , Xenoenxertos , Humanos , Proteínas de Membrana/genética , Camundongos , Camundongos Endogâmicos BALB C , Proteínas Proto-Oncogênicas c-myc/genética , Neoplasias de Mama Triplo Negativas/genética , Neoplasias de Mama Triplo Negativas/metabolismo , Evasão Tumoral , Regulação para Cima
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