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FOXP4 Is a Direct YAP1 Target That Promotes Gastric Cancer Stemness and Drives Metastasis. FOXP4是YAP1的直接靶标,可促进胃癌干细胞生长并推动转移
IF 12.5 1区 医学 Q1 ONCOLOGY Pub Date : 2024-11-04 DOI: 10.1158/0008-5472.CAN-23-3074
Xiaoli Liu, Bonan Chen, Fuda Xie, Kit Yee Wong, Alvin H K Cheung, Jinglin Zhang, Qian Wu, Canbin Fang, Jintao Hu, Shouyu Wang, Dazhi Xu, Jianwu Chen, Yuzhi Wang, Chi Chun Wong, Huarong Chen, William K K Wu, Jun Yu, Michael W Y Chan, Chi Man Tsang, Kwok Wai Lo, Gary M K Tse, Ka-Fai To, Wei Kang

The Hippo-YAP1 pathway is an evolutionally conserved signaling cascade that controls organ size and tissue regeneration. Dysregulation of Hippo-YAP1 signaling promotes initiation and progression of several types of cancer, including gastric cancer. As the Hippo-YAP1 pathway regulates expression of thousands of genes, it is important to establish which target genes contribute to the oncogenic program driven by YAP1 to identify strategies to circumvent it. In this study, we identified a vital role of forkhead box protein 4 (FOXP4) in YAP1-driven gastric carcinogenesis by maintaining stemness and promoting peritoneal metastasis. Loss of FOXP4 impaired gastric cancer spheroid formation and reduced stemness marker expression, whereas FOXP4 upregulation potentiated cancer cell stemness. RNA sequencing analysis revealed SOX12 as a downstream target of FOXP4, and functional studies established that SOX12 supports stemness in YAP1-induced carcinogenesis. A small-molecule screen identified 42-(2-tetrazolyl) rapamycin as a FOXP4 inhibitor, and targeting FOXP4 suppressed gastric cancer tumor growth and enhanced the efficacy of 5-fluorouracil chemotherapy in vivo. Collectively, these findings revealed that FOXP4 upregulation by YAP1 in gastric cancer regulates stemness and tumorigenesis by upregulating SOX12. Targeting the YAP1-FOXP4-SOX12 axis represents a potential therapeutic strategy for gastric cancer. Significance: Hippo-YAP1 signaling maintains stemness in gastric cancer by upregulating FOXP4, identifying FOXP4 as a stemness biomarker and therapeutic target that could help improve patient outcomes.

Hippo-YAP1 通路是一种进化保守的信号级联,它控制着器官的大小和组织的再生。Hippo-YAP1信号传导失调会促进包括胃癌(GC)在内的多种癌症的发生和发展。由于Hippo-YAP1通路调控着数千个基因的表达,因此确定哪些靶基因促成了YAP1驱动的致癌程序以确定规避策略非常重要。在这里,我们确定了 FOXP4 在 YAP1 驱动的胃癌发生中的重要作用,即维持干性和促进腹膜转移。FOXP4缺失会阻碍胃癌球形细胞的形成并减少干性标志物的表达,而FOXP4上调则会增强癌细胞的干性。RNA-seq分析发现SOX12是FOXP4的下游靶标,功能研究证实SOX12在YAP1诱导的癌变中支持干性。小分子筛选发现42-(2-四唑基)雷帕霉素是FOXP4抑制剂,靶向FOXP4可抑制GC肿瘤生长并提高5-FU化疗在体内的疗效。这些发现共同揭示了在GC中YAP1上调FOXP4是通过上调SOX12来调节干性和肿瘤发生的。靶向YAP1-FOXP4-SOX12轴是一种潜在的GC治疗策略。
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引用次数: 0
Targeting BCL2 with Venetoclax Enhances the Efficacy of the KRASG12D Inhibitor MRTX1133 in Pancreatic Cancer. 用 Venetoclax 靶向 BCL2 可增强 KRASG12D 抑制剂 MRTX1133 对胰腺癌的疗效
IF 12.5 1区 医学 Q1 ONCOLOGY Pub Date : 2024-11-04 DOI: 10.1158/0008-5472.CAN-23-3574
Jeffrey H Becker, Anastasia E Metropulos, Christina Spaulding, Alejandra M Marinelarena, Mario A Shields, Daniel R Principe, Thao D Pham, Hidayatullah G Munshi

MRTX1133 is currently being evaluated in patients with pancreatic ductal adenocarcinoma (PDAC) tumors harboring a KRASG12D mutation. Combination strategies have the potential to enhance the efficacy of MRTX1133 to further promote cell death and tumor regression. In this study, we demonstrated that MRTX1133 increased the levels of the proapoptotic protein BIM in PDAC cells and conferred sensitivity to the FDA-approved BCL2 inhibitor venetoclax. Combined treatment with MRTX1133 and venetoclax resulted in cell death and growth suppression in 3D cultures. BIM was required for apoptosis induced by the combination treatment. Consistently, BIM was induced in tumors treated with MRTX1133, and venetoclax enhanced the efficacy of MRTX1133 in vivo. Venetoclax could also resensitize MRTX1133-resistant PDAC cells to MRTX1133 in 3D cultures, and tumors established from resistant cells responded to the combination of MRTX1133 and venetoclax. These results provide a rationale for the clinical testing of MRTX1133 and venetoclax in patients with PDAC. Significance: The combination of MRTX1133 and the FDA-approved drug venetoclax promotes cancer cell death and tumor regression in pancreatic ductal adenocarcinoma, providing rationale for testing venetoclax with KRASG12D inhibitors in patients with pancreatic cancer.

MRTX1133目前正在对携带KRASG12D突变的胰腺导管腺癌(PDAC)患者进行评估。联合策略有可能增强 MRTX1133 的疗效,进一步促进细胞死亡和肿瘤消退。在这项研究中,我们证明了MRTX1133能提高PDAC细胞中促凋亡蛋白BIM的水平,并使细胞对FDA批准的BCL2抑制剂venetoclax敏感。MRTX1133和venetoclax联合治疗可导致细胞死亡,并抑制三维培养物的生长。联合治疗诱导的细胞凋亡需要 BIM。同样,MRTX1133治疗的肿瘤也诱导了BIM,而Venetoclax增强了MRTX1133在体内的疗效。在三维培养中,Venetoclax还能使MRTX1133耐药的PDAC细胞对MRTX1133重新敏感,耐药细胞形成的肿瘤对MRTX1133和venetoclax的联合治疗有反应。这些结果为MRTX1133和venetoclax在PDAC患者中的临床试验提供了依据。
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引用次数: 0
Correction: Quantitative Spatial Profiling of Immune Populations in Pancreatic Ductal Adenocarcinoma Reveals Tumor Microenvironment Heterogeneity and Prognostic Biomarkers. 更正:胰腺导管腺癌免疫群体的定量空间谱分析揭示了肿瘤微环境异质性和预后生物标志物。
IF 12.5 1区 医学 Q1 ONCOLOGY Pub Date : 2024-11-04 DOI: 10.1158/0008-5472.CAN-24-2929
Haoyang Mi, Shamilene Sivagnanam, Courtney B Betts, Shannon M Liudahl, Elizabeth M Jaffee, Lisa M Coussens, Aleksander S Popel
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引用次数: 0
ASCL1 Drives the Development of Neuroendocrine Prostate Cancer. ASCL1 驱动神经内分泌性前列腺癌的发展
IF 12.5 1区 医学 Q1 ONCOLOGY Pub Date : 2024-11-04 DOI: 10.1158/0008-5472.CAN-24-2913
Caden N McQuillen, Nicholas J Brady

Therapeutic resistance to androgen receptor (AR)-targeting agents remains a significant clinical problem during the treatment of prostate cancer, with the incidence rate of resistant disease increasing as more men are treated with next-generation AR-targeted therapies. Lineage plasticity and progression to neuroendocrine prostate cancer (NEPC) are mechanisms by which prostate tumors lose dependence on androgen signaling and escape treatment. Although many known genetic alterations can predispose tumors to acquiring the NEPC phenotype, it remains unclear what, if any, drivers are essential to this progression. In this issue of Cancer Research, Rodarte and colleagues identified ASCL1 as one such essential regulator. Through the use of genetically engineered mouse models, the authors demonstrated that whereas ASCL1 was dispensable for tumor formation and growth, ASCL1 loss nearly completely abrogated the development of NEPC and instead redirected lineage trajectories toward a basal-like phenotype. This study provides an important new model for the study of NEPC, reveals the ability of ASCL1+ NEPC cells to also assume a NEUROD1+ state, and demonstrates the changes to tumor cell phenotypes following ASCL1 loss. See related article by Rodarte et al., p. 3522.

雄激素受体(AR)靶向药物的治疗耐药性仍然是前列腺癌治疗过程中的一个重要临床问题,随着越来越多的男性接受新一代AR靶向疗法,耐药性疾病的发病率也在增加。线型可塑性和进展为神经内分泌性前列腺癌(NEPC)是前列腺肿瘤失去对雄激素信号依赖并逃避治疗的机制。尽管许多已知的基因改变可能导致肿瘤获得 NEPC 表型,但目前仍不清楚这种进展的关键驱动因素是什么。在本期《癌症研究》(Cancer Research)杂志上,Rodarte及其同事发现ASCL1就是这样一种重要的调控因子。通过使用基因工程小鼠模型,作者证明了 ASCL1 对于肿瘤的形成和生长是不可或缺的,而 ASCL1 的缺失则几乎完全抑制了 NEPC 的发展,反而使细胞系轨迹转向基底样表型。这项研究为研究 NEPC 提供了一个重要的新模型,揭示了 ASCL1+ NEPC 细胞也能呈现 NEUROD1+ 状态,并展示了 ASCL1 缺失后肿瘤细胞表型的变化。参见 Rodarte 等人的相关文章,第 3522 页。
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引用次数: 0
Targeting YES1 Disrupts Mitotic Fidelity and Potentiates the Response to Taxanes in Triple-Negative Breast Cancer. 靶向 YES1 可破坏有丝分裂的保真度并增强三阴性乳腺癌对紫杉类药物的反应。
IF 12.5 1区 医学 Q1 ONCOLOGY Pub Date : 2024-11-04 DOI: 10.1158/0008-5472.CAN-23-2558
Katrina M Piemonte, Natasha N Ingles, Kristen L Weber-Bonk, Mitchell J Valentine, Parth R Majmudar, Salendra Singh, Ruth A Keri

Clinical trials examining broad-spectrum Src family kinase (SFK) inhibitors revealed significant dose-limiting toxicities, preventing advancement for solid tumors. SFKs are functionally heterogeneous, thus targeting individual members is a potential strategy to elicit antitumor efficacy while avoiding toxicity. Here, we identified that YES1 is the most highly overexpressed SFK in triple-negative breast cancer (TNBC) and is associated with poor patient outcomes. Disrupting YES1, genetically or pharmacologically, induced aberrant mitosis, centrosome amplification, multipolar spindles, and chromosomal instability. Mechanistically, YES1 sustained FOXM1 protein levels and elevated expression of FOXM1 target genes that control centrosome function and are essential for effective and accurate mitotic progression. In both in vitro and in vivo TNBC models, YES1 suppression potentiated the efficacy of taxanes, cornerstone drugs for TNBC that require elevated chromosomal instability for efficacy. Clinically, elevated expression of YES1 was associated with worse overall survival of patients with TNBC treated with taxane and anthracycline combination regimens. Together, this study demonstrates that YES1 is an essential regulator of genome stability in TNBC that can be leveraged to improve taxane efficacy.  Significance: YES1 is a sentinel regulator of genomic maintenance that controls centrosome homeostasis and chromosome stability through FOXM1, revealing this pathway as a therapeutic vulnerability for enhancing taxane efficacy in triple-negative breast cancer.

对广谱 Src 家族激酶(SFK)抑制剂进行的临床试验显示,这些抑制剂具有明显的剂量限制毒性,阻碍了实体瘤研究的进展。SFK在功能上具有异质性,因此靶向单个成员是一种既能获得抗肿瘤疗效又能避免毒性的潜在策略。在这里,我们发现YES1是三阴性乳腺癌(TNBC)中最高度过表达的SFK,并且与患者的不良预后有关。通过基因或药理学方法破坏 YES1 可诱导异常有丝分裂、中心体扩增、多极纺锤体和染色体不稳定性(CIN)。从机理上讲,YES1 可维持 FOXM1 蛋白水平,并提高 FOXM1 靶基因的表达,而 FOXM1 靶基因可控制中心体功能,对有效和准确的有丝分裂进程至关重要。在体外和体内 TNBC 模型中,YES1 的抑制增强了紫杉类药物的疗效,紫杉类药物是治疗 TNBC 的基础药物,其疗效需要 CIN 升高。在临床上,YES1表达的升高与接受紫杉类药物和蒽环类药物联合治疗的TNBC患者总生存期的缩短有关。总之,这项研究表明,YES1 是 TNBC 基因组稳定性的重要调节因子,可用于提高紫杉类药物的疗效。
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引用次数: 0
FOXR2 targets LHX6+/DLX+ neural lineages to drive CNS neuroblastoma. FOXR2靶向LHX6+/DLX+神经系,驱动中枢神经系统神经母细胞瘤。
IF 12.5 1区 医学 Q1 ONCOLOGY Pub Date : 2024-11-04 DOI: 10.1158/0008-5472.CAN-24-2248
Selin Jessa, Antonella De Cola, Bhavyaa Chandarana, Michael McNicholas, Steven Hébert, Adam Ptack, Damien Faury, Jessica W Tsai, Andrey Korshunov, Timothy N Phoenix, Benjamin Ellezam, David T W Jones, Michael D Taylor, Pratiti Bandopadhayay, Manav Pathania, Nada Jabado, Claudia L Kleinman

Central nervous system neuroblastoma with FOXR2 activation (NB-FOXR2) is a high-grade tumor of the brain hemispheres and a newly identified molecular entity. Tumors express dual neuronal and glial markers, leading to frequent misdiagnoses, and limited information exists on the role of FOXR2 in their genesis. To identify their cellular origins, we profiled the transcriptomes of NB-FOXR2 tumors at the bulk and single-cell levels and integrated these profiles with large single-cell references of the normal brain. NB-FOXR2 tumors mapped to LHX6+/DLX+ lineages derived from the medial ganglionic eminence, a progenitor domain in the ventral telencephalon. In vivo prenatal Foxr2 targeting to the ganglionic eminences in mice induced postnatal cortical tumors recapitulating human NB-FOXR2 specific molecular signatures. Profiling of FOXR2 binding on chromatin in murine models revealed an association with ETS transcriptional networks, as well as direct binding of FOXR2 at key transcription factors that coordinate initiation of gliogenesis. These data indicate that NB-FOXR2 originate from LHX6+/DLX+ interneuron lineages, a lineage-of-origin distinct from that of other FOXR2-driven brain tumors, highlight the susceptibility of ventral telencephalon-derived interneurons to FOXR2-driven oncogenesis, and suggest that FOXR2-induced activation of glial programs may explain the mixed neuronal and oligodendroglial features in these tumors. More broadly, this work underscores systematic profiling of brain development as an efficient approach to orient oncogenic targeting for in vivo modeling, critical for the study of rare tumors and development of therapeutics.

FOXR2激活的中枢神经系统神经母细胞瘤(NB-FOXR2)是大脑半球的一种高级别肿瘤,也是一种新发现的分子实体。肿瘤表达神经元和胶质细胞双重标记物,因此经常被误诊,而关于 FOXR2 在肿瘤发生中的作用的信息也很有限。为了确定它们的细胞起源,我们在大体和单细胞水平上分析了NB-FOXR2肿瘤的转录组,并将这些转录组与正常大脑的大型单细胞参考文献进行了整合。NB-FOXR2肿瘤映射到LHX6+/DLX+细胞系,这些细胞系源自腹侧端脑的内侧神经节突起。体内产前 Foxr2 靶向小鼠神经节突起诱导产后皮质肿瘤,再现了人类 NB-FOXR2 的特异性分子特征。对小鼠模型中染色质上的 FOXR2 结合进行的分析表明,FOXR2 与 ETS 转录网络有关联,并与协调神经胶质生成启动的关键转录因子直接结合。这些数据表明,NB-FOXR2起源于LHX6+/DLX+中间神经元谱系,这一起源谱系与其他FOXR2驱动的脑肿瘤不同,突出了腹侧端脑衍生的中间神经元易受FOXR2驱动的肿瘤发生的影响,并表明FOXR2诱导的神经胶质程序激活可能解释了这些肿瘤中神经元和少突胶质细胞的混合特征。从更广泛的意义上讲,这项工作强调了对大脑发育进行系统剖析是一种有效的方法,可以为体内建模找到致癌靶点,这对罕见肿瘤的研究和治疗方法的开发至关重要。
{"title":"FOXR2 targets LHX6+/DLX+ neural lineages to drive CNS neuroblastoma.","authors":"Selin Jessa, Antonella De Cola, Bhavyaa Chandarana, Michael McNicholas, Steven Hébert, Adam Ptack, Damien Faury, Jessica W Tsai, Andrey Korshunov, Timothy N Phoenix, Benjamin Ellezam, David T W Jones, Michael D Taylor, Pratiti Bandopadhayay, Manav Pathania, Nada Jabado, Claudia L Kleinman","doi":"10.1158/0008-5472.CAN-24-2248","DOIUrl":"https://doi.org/10.1158/0008-5472.CAN-24-2248","url":null,"abstract":"<p><p>Central nervous system neuroblastoma with FOXR2 activation (NB-FOXR2) is a high-grade tumor of the brain hemispheres and a newly identified molecular entity. Tumors express dual neuronal and glial markers, leading to frequent misdiagnoses, and limited information exists on the role of FOXR2 in their genesis. To identify their cellular origins, we profiled the transcriptomes of NB-FOXR2 tumors at the bulk and single-cell levels and integrated these profiles with large single-cell references of the normal brain. NB-FOXR2 tumors mapped to LHX6+/DLX+ lineages derived from the medial ganglionic eminence, a progenitor domain in the ventral telencephalon. In vivo prenatal Foxr2 targeting to the ganglionic eminences in mice induced postnatal cortical tumors recapitulating human NB-FOXR2 specific molecular signatures. Profiling of FOXR2 binding on chromatin in murine models revealed an association with ETS transcriptional networks, as well as direct binding of FOXR2 at key transcription factors that coordinate initiation of gliogenesis. These data indicate that NB-FOXR2 originate from LHX6+/DLX+ interneuron lineages, a lineage-of-origin distinct from that of other FOXR2-driven brain tumors, highlight the susceptibility of ventral telencephalon-derived interneurons to FOXR2-driven oncogenesis, and suggest that FOXR2-induced activation of glial programs may explain the mixed neuronal and oligodendroglial features in these tumors. More broadly, this work underscores systematic profiling of brain development as an efficient approach to orient oncogenic targeting for in vivo modeling, critical for the study of rare tumors and development of therapeutics.</p>","PeriodicalId":9441,"journal":{"name":"Cancer research","volume":null,"pages":null},"PeriodicalIF":12.5,"publicationDate":"2024-11-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142566526","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
KHSRP Stabilizes m6A-Modified Transcripts to Activate FAK Signaling and Promote Pancreatic Ductal Adenocarcinoma Progression. KHSRP 可稳定 m6A 修饰转录本,从而激活 FAK 信号并促进胰腺导管腺癌的进展。
IF 12.5 1区 医学 Q1 ONCOLOGY Pub Date : 2024-11-04 DOI: 10.1158/0008-5472.CAN-24-0927
Zilan Xu, Yifan Zhou, Shaoqiu Liu, Hongzhe Zhao, Ziming Chen, Rui Li, Mei Li, Xudong Huang, Shuang Deng, Lingxing Zeng, Sihan Zhao, Shaoping Zhang, Xiaowei He, Ji Liu, Chunling Xue, Ruihong Bai, Lisha Zhuang, Quanbo Zhou, Rufu Chen, Dongxin Lin, Jian Zheng, Jialiang Zhang

N 6-Methyladenosine (m6A) is the most prevalent RNA modification and is associated with various biological processes. Proteins that function as readers and writers of m6A modifications have been shown to play critical roles in human malignancies. Here, we identified KH-type splicing regulatory protein (KHSRP) as an m6A binding protein that contributes to the progression of pancreatic ductal adenocarcinoma (PDAC). High KHSRP levels were detected in PDAC and predicted poor patient survival. KHSRP deficiency suppressed PDAC growth and metastasis in vivo. Mechanistically, KHSRP recognized and stabilized FAK pathway mRNAs, including MET, ITGAV, and ITGB1, in an m6A-dependent manner, which led to activation of downstream FAK signaling that promoted PDAC progression. Targeting KHSRP with a PROTAC showed promising tumor suppressive effects in mouse models, leading to prolonged survival. Together, these findings indicate that KHSRP mediates FAK pathway activation in an m6A-dependent manner to support PDAC growth and metastasis, highlighting the potential of KHSRP as a therapeutic target in pancreatic cancer. Significance: KHSRP is a m6A-binding protein that stabilizes expression of FAK pathway mRNAs and that can be targeted to suppress FAK signaling and curb pancreatic ductal adenocarcinoma progression.

N6-甲基腺苷(m6A)是最常见的 RNA 修饰,与各种生物过程有关。作为 m6A 修饰的阅读者和书写者的蛋白质已被证明在人类恶性肿瘤中发挥关键作用。在这里,我们发现 KH 型剪接调控蛋白(KHSRP)是一种 m6A 结合蛋白,它有助于胰腺导管腺癌(PDAC)的进展。在 PDAC 中检测到高水平的 KHSRP,这预示着患者的生存率很低。KHSRP 缺乏会抑制 PDAC 在体内的生长和转移。从机理上讲,KHSRP以m6A依赖的方式识别并稳定FAK通路mRNA,包括MET、ITGAV和ITGB1,从而激活下游FAK信号,促进PDAC的进展。用 PROTAC 靶向 KHSRP 在小鼠模型中显示出良好的抑瘤效果,从而延长了生存期。这些发现共同表明,KHSRP以m6A依赖性方式介导FAK通路激活,支持PDAC的生长和转移,凸显了KHSRP作为胰腺癌治疗靶点的潜力。
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引用次数: 0
H3K18 Lactylation Potentiates Immune Escape of Non-Small Cell Lung Cancer. H3K18 乳化能增强非小细胞肺癌的免疫逃逸能力
IF 12.5 1区 医学 Q1 ONCOLOGY Pub Date : 2024-11-04 DOI: 10.1158/0008-5472.CAN-23-3513
Cai Zhang, Lijie Zhou, Mingyuan Zhang, Yue Du, Cai Li, Huijun Ren, Lu Zheng

Recently discovered epigenetic modification lysine lactylation contributes to tumor development and progression in several types of cancer. In addition to the tumor-intrinsic effects, histone lactylation may mediate tumor microenvironment remodeling and immune evasion. In this study, we observed elevated pan-lysine lactylation and histone H3 lysine 18 lactylation (H3K18la) levels in non-small cell lung cancer (NSCLC) tissues, which was positively correlated with poor patient prognosis. Interruption of glycolysis by 2-deoxy-D-glucose and oxamate treatment and silencing of lactate dehydrogenase A and lactate dehydrogenase B reduced H3K18la levels and circumvented immune evasion of NSCLC cells by enhancing CD8+ T-cell cytotoxicity. Mechanistically, H3K18la directly activated the transcription of pore membrane protein 121 (POM121), which enhanced MYC nuclear transport and direct binding to the CD274 promoter to induce PD-L1 expression. In a mouse NSCLC xenograft model, combination therapy with a glycolysis inhibitor and an anti-PD-1 antibody induced intratumoral CD8+ T-cell function and exhibited strong antitumor efficacy. Overall, this work revealed that H3K18la potentiates the immune escape of NSCLC cells by activating the POM121/MYC/PD-L1 pathway, which offers insights into the role of posttranslational modifications in carcinogenesis and provides a rationale for developing an epigenetic-targeted strategy for treating NSCLC. Significance: H3K18 lactylation supports immunosuppression in non-small cell lung cancer by inducing POM121 to increase MYC activity and PD-L1 expression, which can be reversed by metabolic reprogramming and immunotherapy treatment.

最近发现的表观遗传修饰赖氨酸乳酰化(Kla)在几种类型的癌症中对肿瘤的发展和恶化起到了促进作用。除了肿瘤内在影响外,组蛋白乳化还可能介导肿瘤微环境重塑和免疫逃避。在这里,我们观察到非小细胞肺癌(NSCLC)组织中pan Kla和H3K18la水平升高,这与患者预后不良呈正相关。通过2-DG和草氨酸处理中断糖酵解以及沉默LDHA和LDHB可降低H3K18la水平,并通过增强CD8+ T细胞的细胞毒性来规避NSCLC细胞的免疫逃避。从机制上讲,H3K18la直接激活了POM121的转录,从而增强了MYC的核转运,并直接与CD274启动子结合,诱导PD-L1的表达。在小鼠NSCLC异种移植模型中,糖酵解抑制剂和抗PD-1抗体的联合疗法诱导了瘤内CD8+ T细胞功能,并显示出很强的抗肿瘤疗效。总之,这项研究揭示了H3K18la通过激活POM121/MYC/PD-L1通路增强了NSCLC细胞的免疫逃逸能力,从而深入揭示了翻译后修饰在致癌过程中的作用,并为开发治疗NSCLC的表观遗传靶向策略提供了理论依据。
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引用次数: 0
PRDM16 Induces Methylation of FLT3 to Promote FLT3-ITD Signaling and Leukemia Progression. PRDM16 诱导 FLT3 甲基化,促进 FLT3-ITD 信号转导和白血病进展
IF 12.5 1区 医学 Q1 ONCOLOGY Pub Date : 2024-11-04 DOI: 10.1158/0008-5472.CAN-24-0577
Fengxian Zhai, Guozheng Pan, Lei Xue, Can Cheng, Jiabei Wang, Yao Liu, Lianxin Liu

Internal tandem duplication (ITD) in the FMS-like receptor tyrosine kinase-3 (FLT3) is one of the most frequent mutations in acute myeloid leukemia (AML) and is associated with poor prognosis. FLT3-ITD mutations result in endoplasmic reticulum (ER) retention and constitutive autophosphorylation of FLT3. The PR/SET domain 16 (PRDM16) is highly expressed in FLT3-ITD+ AML patients, suggesting it might play a role in leukemogenesis. Here, we revealed that genetic and pharmacological suppression of PRDM16 greatly slowed the progression of FLT3-ITD-driven leukemia, sensitized leukemic cells to tyrosine kinase inhibitors (TKIs), and extended the survival of leukemic mice. PRDM16 enhanced activation of oncogenic FLT3-ITD and ligand-dependent activation of wild-type FLT3 in leukemic cells. Mechanistically, PRDM16 mediated monomethylation of FLT3-ITD at lysine 614 and promoted its ER localization, resulting in enhanced FLT3 signaling in leukemia cells. Moreover, pharmacological suppression of FLT3-ITD methylation in combination with TKIs increased the elimination of FLT3-ITD+ AML cells. Altogether, these results suggest that PRDM16 boosts oncogenic FLT3 signaling in leukemic cells by prompting FLT3-ITD methylation. Therefore, PRDM16 may serve as a therapeutic target for AML.

FMS样受体酪氨酸激酶-3(FLT3)的内部串联重复(ITD)是急性髓性白血病(AML)中最常见的突变之一,与预后不良有关。FLT3-ITD突变导致内质网(ER)滞留和FLT3组成性自磷酸化。PR/SET结构域16(PRDM16)在FLT3-ITD+ AML患者中高表达,表明它可能在白血病发生中发挥作用。在这里,我们发现遗传和药物抑制 PRDM16 可大大减缓 FLT3-ITD 驱动的白血病的进展,使白血病细胞对酪氨酸激酶抑制剂(TKIs)敏感,并延长白血病小鼠的存活时间。PRDM16 增强了白血病细胞中致癌 FLT3-ITD 的活化和野生型 FLT3 的配体依赖性活化。从机理上讲,PRDM16介导了FLT3-ITD赖氨酸614处的单甲基化,并促进了其ER定位,从而增强了白血病细胞中的FLT3信号转导。此外,药物抑制 FLT3-ITD 甲基化与 TKIs 联用可增加对 FLT3-ITD+ AML 细胞的清除。总之,这些结果表明,PRDM16 通过促使 FLT3-ITD 甲基化,促进了白血病细胞中的致癌 FLT3 信号转导。因此,PRDM16 可作为急性髓细胞白血病的治疗靶点。
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引用次数: 0
Targeting Catechol-O-Methyltransferase Induces Mitochondrial Dysfunction and Enhances the Efficacy of Radiotherapy in Glioma. 靶向儿茶酚-O-甲基转移酶可诱导线粒体功能障碍并提高胶质瘤放疗的疗效
IF 12.5 1区 医学 Q1 ONCOLOGY Pub Date : 2024-11-04 DOI: 10.1158/0008-5472.CAN-24-0134
Meng Jiao, Christopher J Pirozzi, Chen Yu, Xuhui Bao, Mengjie Hu, Dong Pan, Sejiro Littleton, Nathan Reynolds, Daniel R Saban, Fang Li, Chuan-Yuan Li

Radiotherapy (RT) is commonly used to try to eliminate any remaining tumor cells following surgical resection of glioma. However, tumor recurrence is prevalent, highlighting the unmet medical need to develop therapeutic strategies to enhance the efficacy of RT in glioma. Focusing on the radiosensitizing potential of the currently approved drugs known to cross the blood-brain barrier can facilitate rapid clinical translation. Here, we assessed the role of catechol-O-methyltransferase (COMT), a key enzyme to degrade catecholamines and a drug target for Parkinson's disease, in glioma treatment. Analysis of The Cancer Genome Atlas data showed significantly higher COMT expression levels in both low-grade glioma and glioblastoma compared to normal brain tissues. Inhibition of COMT by genetic knockout or FDA-approved COMT inhibitors significantly sensitized glioma cells to RT in vitro and in vivo. Mechanistically, COMT inhibition in glioma cells led to mitochondria dysfunction and increased mitochondrial RNA release into the cytoplasm, activating the cellular antiviral double-stranded RNA sensing pathway and type I interferon (IFN) response. Elevated type I IFNs stimulated the phagocytic capacity of microglial cells, enhancing RT efficacy. Given the long-established safety record of the COMT inhibitors, these findings provide a solid rationale to evaluate them in combination with RT in patients with glioma. Significance: Inhibition of catechol-O-methyltransferase, a well-established drug target in Parkinson's disease, interferes with mitochondrial electron transport and induces mitochondrial double-stranded RNA leakage, activating type I interferon signaling and sensitizing glioma to radiotherapy.

放疗(RT)通常用于消除胶质瘤手术切除后残留的肿瘤细胞。然而,肿瘤复发是普遍现象,这凸显了开发治疗策略以提高神经胶质瘤放疗疗效的医疗需求尚未得到满足。关注目前已获批准的已知可穿过血脑屏障的药物的放射增敏潜力可促进快速临床转化。在这里,我们评估了儿茶酚-邻甲基转移酶(COMT)在胶质瘤治疗中的作用,它是降解儿茶酚胺的关键酶,也是帕金森病的药物靶点。TCGA数据分析显示,与正常脑组织相比,低级别胶质瘤和胶质母细胞瘤的COMT表达水平明显更高。通过基因敲除或FDA批准的COMT抑制剂抑制COMT,可使胶质瘤细胞在体外和体内对RT显著敏感。从机理上讲,抑制胶质瘤细胞中的 COMT 会导致线粒体功能障碍,增加线粒体 RNA 向细胞质的释放,激活细胞的抗病毒双链 RNA 传感途径和 I 型干扰素(IFN)反应。I 型干扰素的升高刺激了小胶质细胞的吞噬能力,增强了 RT 的疗效。考虑到 COMT 抑制剂长期以来建立的安全记录,这些发现为评估它们与 RT 联合治疗胶质瘤患者提供了可靠的依据。
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