Neoplasia最新文献_第8页

Genomic landscape and molecular evolutionary trajectories of renal epithelioid angiomyolipoma and benign angiomyolipoma 肾上皮样血管平滑肌脂肪瘤和良性血管平滑肌脂肪瘤的基因组图谱和分子进化轨迹

IF 4.8 2区医学 Q1 Biochemistry, Genetics and Molecular Biology

Neoplasia

Pub Date : 2025-10-01 Epub Date: 2025-07-23 DOI: 10.1016/j.neo.2025.101212

Aihetaimujiang Anwaier , Yuanyuan Qu , Shiqi Ye , Xi Tian , Shuxuan Zhu , Siqi Zhou , Guohai Shi , Yu Zhu , Hailiang Zhang , Dingwei Ye , Wenhao Xu

Renal angiomyolipoma (AML) encompasses benign variants (lipomatous [L-AML], myomatous [M-AML]) and epithelioid AML (eAML), a potentially malignant subtype associated with aggressive behavior. While TSC1/TSC2 mutations are frequent, the molecular drivers underlying eAML pathogenesis remain unclear. Whole-exome sequencing (WES) was performed on 35 AML samples (15 eAML, 10 L-AML, 10 M-AML) with matched germline controls. Driver genes were identified using OncodriveCLUST and MutSigCV. Validation was conducted on 71 FFPE samples integrating expression profiling and survival analysis. The finding suggested that TSC2 emerged as the most frequently mutated pathogenic gene in AML, exhibiting a mutation rate of 69 %. TSC2, POLDIP2, NEFH, and MUC2 emerged as potential driver genes across AML subtypes, whereas RHPN2, ASXL1, TOP3B, and USP35 showed subtype-specific mutations. Notably, distinct cytogenetic aberrations were observed among AML variants, including deletions at 3p26.3, 5p13.1, 6p22.1, and 11p11.11. Clonal evolution analysis suggested that l-AML and eAML, as well as M-AML and eAML, may originate from a common ancestral clone, retaining early mutations and acquiring additional alterations post-divergence. Low TSC2/POLDIP2 and high NEFH/MUC2 expression correlated with favorable survival in eAML patients. Importantly, lower TSC2/POLDIP2 expression also predicted superior response rates to Everolimus therapy. In conclusion, our study comprehensively delineates genomic distinctions and evolutionary trajectories among renal AML subtypes, establishing TSC2, POLDIP2, NEFH, and MUC2 as prognostic biomarkers and therapeutic predictors, facilitating precision medicine in eAML management.

肾血管平滑肌脂肪瘤（AML）包括良性变种（脂肪瘤型[L-AML]，肌瘤型[M-AML]）和上皮样AML (eAML)，这是一种潜在的恶性亚型，与侵袭行为相关。虽然TSC1/TSC2突变很常见，但eAML发病机制的分子驱动因素尚不清楚。对35份AML样本（15份eAML， 10份L-AML， 10份M-AML）进行了全外显子组测序（WES），并进行了匹配的种系对照。使用OncodriveCLUST和MutSigCV鉴定驱动基因。结合表达谱和生存分析对71例FFPE样本进行验证。这一发现表明，TSC2是AML中最常见的突变致病基因，突变率为69%。TSC2、POLDIP2、NEFH和MUC2是AML亚型的潜在驱动基因，而RHPN2、ASXL1、TOP3B和USP35表现出亚型特异性突变。值得注意的是，在AML变体中观察到明显的细胞遗传学畸变，包括3p26.3, 5p13.1, 6p22.1和11p11.11缺失。克隆进化分析表明，l-AML和eAML，以及M-AML和eAML可能起源于一个共同的祖先克隆，保留了早期突变，并在分化后获得了额外的改变。低TSC2/POLDIP2和高NEFH/MUC2表达与eAML患者的有利生存相关。重要的是，较低的TSC2/POLDIP2表达也预示着依维莫司治疗的更高应答率。总之，我们的研究全面描述了肾性AML亚型之间的基因组差异和进化轨迹，建立了TSC2、POLDIP2、NEFH和MUC2作为预后生物标志物和治疗预测因子，促进了肾性AML治疗的精准医学。

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引用次数: 0

Prkci activates Jak2/Stat3 signaling to promote tumor angiogenesis Prkci激活Jak2/Stat3信号，促进肿瘤血管生成

IF 7.7 2区医学 Q1 Biochemistry, Genetics and Molecular Biology

Neoplasia

Pub Date : 2025-10-01 Epub Date: 2025-08-20 DOI: 10.1016/j.neo.2025.101219

Peng Li , Guangshi Liu , Wenbin Zhang , Tao Li , Xinhui Yang

Background

Tumor angiogenesis is essential for colorectal cancer (CRC) progression, providing oxygen and nutrients to sustain tumor growth and metastasis. Protein kinase C iota (Prkci) is an atypical protein kinase known for its oncogenic roles in various cancers; however, its function in CRC angiogenesis remains largely unexplored. This study investigates the role of Prkci in regulating tumor angiogenesis through the Jak2/Stat3 signaling pathway.

Methods

Prkci expression levels in CRC tissues and their correlation with micro-vessel density and patient prognosis were analyzed. Functional experiments, including endothelial cell proliferation, migration, and tube formation assays, were performed in vitro to assess the angiogenic effects of Prkci. In vivo, a CRC xenograft mouse model with Prkci knockout was used to evaluate tumor growth and angiogenesis. Mechanistic studies explored how Prkci activates Jak2 by phosphorylating it at the S633 site, leading to downstream Stat3 activation and Vegfa expression.

Results

Prkci was upregulated in CRC tissues and correlated with increased micro-vessel density and poor patient prognosis. In vitro, Prkci overexpression enhanced endothelial cell proliferation, migration, and tube formation, while Prkci knockout inhibited these processes. Mechanistically, Prkci phosphorylated Jak2 at S633, leading to enhanced Stat3 activation and increased Vegfa expression, which promoted angiogenesis. In vivo, Prkci knockout in CRC cells significantly reduced tumor growth, angiogenesis, and prolonged survival in a mouse model.

Conclusions

These findings identify Prkci as a key regulator of angiogenesis in CRC through Jak2/Stat3 signaling activation. Targeting Prkci could provide a novel therapeutic approach to inhibit tumor angiogenesis and limit CRC progression.

肿瘤血管生成是结直肠癌（CRC）发展的必要条件，为维持肿瘤生长和转移提供氧气和营养。蛋白激酶C - iota （Prkci）是一种非典型的蛋白激酶，因其在各种癌症中的致癌作用而闻名；然而，其在结直肠癌血管生成中的功能在很大程度上仍未被探索。本研究探讨了Prkci通过Jak2/Stat3信号通路调控肿瘤血管生成的作用。方法分析sprkci在结直肠癌组织中的表达水平及其与微血管密度和患者预后的关系。功能实验，包括内皮细胞增殖、迁移和试管形成实验，在体外进行，以评估Prkci的血管生成作用。在体内，Prkci基因敲除的CRC异种移植小鼠模型被用来评估肿瘤生长和血管生成。机制研究探索了Prkci如何通过在S633位点磷酸化Jak2来激活Jak2，从而导致下游Stat3激活和vegf表达。结果sprkci在结直肠癌组织中表达上调，与微血管密度增高和患者预后不良相关。在体外，Prkci过表达增强了内皮细胞的增殖、迁移和管的形成，而敲除Prkci则抑制了这些过程。从机制上讲，Prkci使Jak2在S633位点磷酸化，导致Stat3活化增强和Vegfa表达增加，从而促进血管生成。在小鼠模型中，敲除CRC细胞中的Prkci可显著降低肿瘤生长、血管生成和延长存活时间。结论通过Jak2/Stat3信号激活，Prkci是CRC血管生成的关键调控因子。靶向Prkci可提供抑制肿瘤血管生成和限制结直肠癌进展的新治疗方法。

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引用次数: 0

Proteomic characterization of the pseudocapsule of clear cell renal cell carcinoma in VHL disease reveals a distinct microenvironment at the tumor boundary zone VHL疾病透明细胞肾细胞癌假包膜的蛋白质组学特征揭示了肿瘤边界区独特的微环境

IF 7.7 2区医学 Q1 Biochemistry, Genetics and Molecular Biology

Neoplasia

Pub Date : 2025-10-01 Epub Date: 2025-08-05 DOI: 10.1016/j.neo.2025.101214

Tobias Feilen , Manuel Rogg , Grigor Andreev , Niko Pinter , Maximilian Wess , Anna L. Kössinger , Nastasja Diel , Elke Neumann-Haefelin , Athina Ganner , Markus Grabbert , Christoph Schell , Oliver Schilling

Von Hippel-Lindau (VHL) disease describes a hereditary tumor predisposition syndrome, caused by germline mutations in the VHL tumor suppressor gene, resulting in the functional loss of the VHL protein (pVHL). pVHL loss translates into a pseudo-hypoxic state that drives clear cell renal cell carcinoma (ccRCC) development. ccRCC tumors frequently form a pseudocapsule (PC) at the tumor boundary. This study describes the first comprehensive proteomic analysis of the PC in ccRCC patients with hereditary VHL inactivation, revealing a distinctive matrisomal signature. We conducted a deep, mass spectrometry-based proteomic analysis of 130 formalin-fixed paraffin-embedded (FFPE) ccRCC samples, comprising 54 tumor, 45 PC, and 31 non-malignant adjacent tissue (NAT) specimens from 34 patients. The PC exhibited unique matrisomal features, with pronounced enrichment of structural extracellular matrix (ECM) components, ECM processing enzymes, and secreted signaling proteins such as TGFβ2. Its proteome composition, including proteins involved in immune response, varied with tumor size and semi-tryptic peptide analysis indicated selective ECM processing in the PC and elevated levels of proteolysis within the tumor. Further, tumor proteomes reflected canonical VHL-driven metabolic reprogramming, including upregulated glycolysis and hypoxia markers, suppressed aerobic metabolism, and dysregulated fatty acid metabolism. Enriched immunoproteasome, MHC-I, and inflammasome proteins indicated an active immune response. Pro-angiogenic factors enriched in the tumor partially extended into the PC. Comparison of primary vs metachronous ccRCC cases uncovered proteomic tumor plasticity in VHL disease. Together, our study delineates the PC as an active, signaling-rich compartment at the ccRCC boundary with potential implications for tumor progression and clinical relevance beyond a mere structural scaffold.

Von Hippel-Lindau （VHL）病描述了一种遗传性肿瘤易感性综合征，由VHL肿瘤抑制基因的种系突变引起，导致VHL蛋白（pVHL）的功能丧失。pVHL缺失转化为假性缺氧状态，驱动透明细胞肾细胞癌（ccRCC）的发展。ccRCC肿瘤常在肿瘤边界形成假包膜（PC）。这项研究首次对遗传性VHL失活的ccRCC患者的PC进行了全面的蛋白质组学分析，揭示了一个独特的基质特征。我们对来自34例患者的130例福尔马林固定石蜡包埋（FFPE） ccRCC样本进行了深入的、基于质谱的蛋白质组学分析，其中包括54例肿瘤、45例PC和31例非恶性邻近组织（NAT）样本。PC表现出独特的基质特征，其结构细胞外基质（ECM）成分、ECM加工酶和分泌的信号蛋白如tgf - β2显著富集。它的蛋白质组组成，包括参与免疫反应的蛋白质，随着肿瘤大小的变化而变化，半色氨酸肽分析表明，PC中选择性ECM加工和肿瘤内蛋白水解水平升高。此外，肿瘤蛋白质组反映了典型的vhl驱动的代谢重编程，包括糖酵解和缺氧标记上调、有氧代谢抑制和脂肪酸代谢失调。丰富的免疫蛋白酶体、mhc - 1和炎性小体蛋白表明免疫反应活跃。肿瘤中富集的促血管生成因子部分延伸至前列腺癌。原发性和异时性ccRCC病例的比较揭示了VHL疾病中蛋白质组学肿瘤的可塑性。总之，我们的研究将PC描述为ccRCC边界上一个活跃的、富含信号的隔室，它对肿瘤进展和临床相关性具有潜在的影响，而不仅仅是一个结构支架。

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引用次数: 0

A methyl-to-acetyl switch in H3K27 drives metabolic reprogramming and resistance to BRAFV600E inhibition in melanoma 在黑色素瘤中，H3K27中的甲基-乙酰开关驱动代谢重编程和对BRAFV600E抑制的抗性

IF 7.7 2区医学 Q1 Biochemistry, Genetics and Molecular Biology

Neoplasia

Pub Date : 2025-10-01 Epub Date: 2025-08-23 DOI: 10.1016/j.neo.2025.101223

Jiang Zhou , Xinxin Chai , Yi Zhu , Zhi Huang , Tingting Lin , Zhen Hu , Guangdi Chen , Chi Luo , Rutao Cui , Jinghao Sheng

The BRAF^V600E pathway and epigenetic machinery are central to melanoma pathogenesis. However, how these processes intersect and their potential for synthetic lethality remains unclear. Here, we identified a BRAF^V600E-driven epigenetic mechanism in melanoma that involves a H3K27 methylation-to-acetylation switch, facilitating metabolic adaptation to targeted therapies. Inhibition of BRAF^V600E downregulates the methyltransferase EZH2, leading to KDM6A-mediated removal of H3K27me3 and a subsequent increase in H3K27 acetylation (H3K27ac). This H3K27 methyl-to-acetyl conversion shifts chromatin from a repressive to an active state, thereby promoting gene transcription through the acetylation reader BRD4. Specifically, the KDM6A-H3K27ac-BRD4 axis upregulates PGC1α, a master regulator of mitochondrial metabolism, enabling melanoma cells to sustain oxidative metabolism and survive BRAF^V600E-targeted therapies. Blocking this H3K27 methyl-to-acetyl switch disrupted metabolic adaptation and sensitized melanoma cells to BRAF^V600E inhibition. In conclusion, we revealed an epigenetic and metabolic reprogramming mechanism that enables melanoma to survive the treatment with BRAF^V600E inhibitors, presenting druggable targets within the H3K27 modification pathway that could enhance the efficacy of BRAF-targeted therapies in melanoma patients.

BRAFV600E通路和表观遗传机制是黑色素瘤发病的核心。然而，这些过程如何交叉以及它们潜在的合成致命性仍不清楚。在这里，我们确定了黑色素瘤中brafv600e驱动的表观遗传机制，涉及H3K27甲基化到乙酰化开关，促进代谢适应靶向治疗。BRAFV600E的抑制下调了甲基转移酶EZH2，导致kdm6a介导的H3K27me3的去除和随后H3K27乙酰化（H3K27ac）的增加。这种H3K27甲基-乙酰化转化将染色质从抑制状态转变为活性状态，从而通过乙酰化解读器BRD4促进基因转录。具体来说，KDM6A-H3K27ac-BRD4轴上调线粒体代谢的主要调节因子PGC1α，使黑色素瘤细胞能够维持氧化代谢并在brafv600e靶向治疗中存活。阻断这种H3K27甲基-乙酰开关破坏了代谢适应，使黑色素瘤细胞对BRAFV600E抑制敏感。总之，我们揭示了一种表观遗传和代谢重编程机制，使黑色素瘤能够在BRAFV600E抑制剂的治疗中存活下来，并在H3K27修饰途径中提出了可药物靶点，可以增强braf靶向治疗黑色素瘤患者的疗效。

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引用次数: 0

Screening and identification of HLA-A2-restricted neoepitopes for immunotherapy in endocrine therapy-resistant breast cancer 内分泌治疗抵抗性乳腺癌免疫治疗hla - a2限制性新表位的筛选和鉴定

IF 4.8 2区医学 Q1 Biochemistry, Genetics and Molecular Biology

Neoplasia

Pub Date : 2025-09-01 Epub Date: 2025-06-23 DOI: 10.1016/j.neo.2025.101200

Mingshuang Wang , Liwei Pang , Yingjie Sun , Jingjing Han , Jiani Fan , Wenhui Shen , Xiaonan Hu , Bingqian Yang , Haoming Ning , Yanan Kong , Duo Li , Wenshan Zhao , Ranran Shi , Ling Ran , Yuanming Qi , Yahong Wu

Endocrine therapy has shown significant clinical efficacy in estrogen receptor alpha (ERα)-positive breast cancer management, but the emergence of therapy-resistant mutations significantly undermines treatment outcomes, frequently leading to disease progression and metastasis. Among these resistance mechanisms, mutations in the ESR1 gene are particularly prevalent, detectable in 76% of endocrine therapy-resistant tumor specimens. The identification of immunogenic neoepitopes derived from mutant ESR1 offers a promising therapeutic avenue for patients with endocrine therapy-resistant breast cancer. In this study, we systematically investigated the mutational landscape of ESR1 across various cancer types, with particular emphasis on mutation frequency and spectrum analysis. Our findings revealed that non-synonymous ESR1 mutations predominantly occurred in breast cancer, clustering at four distinct hotspot sites: K303, E380, Y537 and D538. We further characterized the mutation prevalence at these hotspots across different breast cancer subtypes. Through comprehensive screening, we identified eight human leukocyte antigen (HLA)-A*0201 restricted immunogenic neoepitopes derived from ESR1 hotspot mutations. These neoepitopes demonstrated the capacity to elicit specific cytotoxic T lymphocytes (CTLs) responses both in vitro and in vivo. The induced CTLs exhibited specific recognition and cytotoxic activity against both T2A2 cells loaded with mutant neoepitopes and HLA-A*0201-positive breast cancer cells transfected with minigene encoding mutant neoepitopes. Notably, adoptive transfer of T cells primed with a peptide pool containing these eight neoepitopes significantly suppressed tumor growth and enhanced CD8⁺ T cells infiltration within tumor tissue. These findings suggest that the identified neoepitopes represent promising candidates for the development of tumor shared neoantigen vaccines.

内分泌治疗在雌激素受体α (ERα)阳性乳腺癌治疗中显示出显著的临床疗效，但治疗耐药突变的出现显著破坏了治疗结果，经常导致疾病进展和转移。在这些耐药机制中，ESR1基因的突变尤其普遍，在76%的内分泌治疗耐药肿瘤标本中可检测到。来自突变体ESR1的免疫原性新表位的鉴定为内分泌治疗抵抗性乳腺癌患者提供了一条有希望的治疗途径。在这项研究中，我们系统地研究了ESR1在各种癌症类型中的突变景观，特别强调突变频率和频谱分析。我们的研究结果显示，非同义ESR1突变主要发生在乳腺癌中，聚集在四个不同的热点位点：K303、E380、Y537和D538。我们进一步描述了不同乳腺癌亚型在这些热点的突变流行率。通过综合筛选，我们从ESR1热点突变中鉴定出8个人类白细胞抗原(HLA)-A*0201限制性免疫原性新表位。这些新表位在体内和体外都能引起特异性的细胞毒性T淋巴细胞（ctl）反应。诱导的ctl对携带突变新表位的T2A2细胞和携带编码突变新表位的minigene的HLA-A*0201阳性乳腺癌细胞均表现出特异性识别和细胞毒活性。值得注意的是，用含有这8个新表位的肽池启动的T细胞过继转移可显著抑制肿瘤生长并增强CD8+ T细胞在肿瘤组织中的浸润。这些发现表明，已鉴定的新表位代表了开发肿瘤共享新抗原疫苗的有希望的候选者。

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引用次数: 0

Hepatocellular carcinoma escapes immune surveillance through deceiving thymus into recalling peripheral activated CD8+ T cells 肝细胞癌通过欺骗胸腺召回外周活化的CD8+ T细胞来逃避免疫监视

IF 4.8 2区医学 Q1 Biochemistry, Genetics and Molecular Biology

Neoplasia

Pub Date : 2025-09-01 Epub Date: 2025-07-18 DOI: 10.1016/j.neo.2025.101210

Qiaoting Hu , Xuefeng Wang , Yundan You , Jun Liu , Bin Lan , Fangfang Chen , Hong Wen , Haili Cheng , Weibin Zhuo , Ting Xu , Jingxian Zheng , Yuchuan Jiang , Xiaojie Wang , Jing Lin , Zengqing Guo , Sha Huang , Gang Chen , Yu Chen , Jingfeng Liu

The role of thymic epithelial cells (TECs) in eliminating self-reactive T cells through the presentation of self-antigens is well-established. However, it remains unclear whether TECs can eliminate tumor-reactive CD8⁺ T cells by presenting tumor antigens. In this study, we observed that CD73⁺ Granzyme B⁺ peripheral activated CD8⁺ T cells undergo apoptosis in the medullary region of the thymus in DEN-CCL₄-induced spontaneous HCC mice, but not in the naïve control group. Mechanistically, HCC cells manipulate the thymus to recruit peripheral activated CD8⁺ T cells through the CCL19/CCL21-CCR7 axis. Additionally, TECs capture antigens from HCC cells for subsequent antigen presentation instead of de novo expressing tumor antigens. When tumor-associated CD8⁺ T cells homing to the thymus recognize the same tumor antigen presented by TECs, activation-induced cell death (AICD) is initiated in these T cells. Thymectomy redistributes CD8⁺ T cells into the tumor focus to suppress HCC growth. Alternatively, both inhibiting CCL19/CCL21 expression of thymic cells using an AMPK activator and blocking CCR7 on CD8⁺ T cells binding with ligands using Cmp2105 significantly reduces tumor-educated thymus dependent immune evasion. Our findings collectively demonstrate that HCC manipulates the thymus to trigger immune escape; pharmacologically targeting CCL19/CCL21-CCR7 axis to inhibit thymus homing can increase CD8⁺ T cells in the tumor microenvironment.

胸腺上皮细胞（TECs）通过呈递自身抗原来消除自身反应性T细胞的作用已得到证实。然而，目前尚不清楚TECs是否可以通过呈递肿瘤抗原来消除肿瘤反应性CD8+ T细胞。在本研究中，我们观察到CD73+颗粒酶B+外周活化的CD8+ T细胞在den - ccl4诱导的自发性HCC小鼠胸腺髓质区发生凋亡，但在naïve对照组中没有。机制上，HCC细胞通过CCL19/CCL21-CCR7轴操纵胸腺募集外周活化的CD8+ T细胞。此外，tec从HCC细胞中捕获抗原用于随后的抗原呈递，而不是从头表达肿瘤抗原。当归巢到胸腺的肿瘤相关CD8+ T细胞识别由TECs呈递的相同肿瘤抗原时，激活诱导细胞死亡（AICD）在这些T细胞中启动。胸腺切除术将CD8+ T细胞重新分配到肿瘤病灶以抑制HCC的生长。另外，使用AMPK激活剂抑制胸腺细胞CCL19/CCL21的表达，以及使用Cmp2105阻断CD8+ T细胞上与配体结合的CCR7，均可显著减少肿瘤诱导的胸腺依赖性免疫逃避。我们的研究结果共同表明，HCC操纵胸腺触发免疫逃逸；药理学上靶向CCL19/CCL21-CCR7轴抑制胸腺归巢可增加肿瘤微环境中的CD8+ T细胞。

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引用次数: 0

The TRIM22-CDT2 axis is the key mediator of the p53-Rb signals in growth control of HPV-positive cervical carcinoma cells TRIM22-CDT2轴是p53-Rb信号在hpv阳性宫颈癌细胞生长控制中的关键介质

IF 4.8 2区医学 Q1 Biochemistry, Genetics and Molecular Biology

Neoplasia

Pub Date : 2025-09-01 Epub Date: 2025-07-17 DOI: 10.1016/j.neo.2025.101211

Qing Zhou , Hongfei Yu , Anliang Dong , Jiani Yi , Jia Li , Xufan Li , Liyuan Zhou , Qiongzi Qiu , Bingjian Lu , Honghe Zhang , Weiguo Lu , Yi Sun , Pengyuan Liu , Yan Lu

Persistent infection with high-risk human papillomavirus (HPV) is the primary contributor to the development of cervical cancer. Although HPV oncoproteins E6 and E7 clearly trigger cervical tumorigenesis by inactivating p53 and Rb pathways, the downstream mediators of p53/Rb inactivation remain elusive. Here we report that CDT2, a subunit of Cullin-RING ligase 4 (CRL4), is significantly upregulated in cervical carcinoma tissues, which correlates with E6/E7 expression and poor patient survival. Mechanistically, E7-mediated Rb degradation upregulates E2F1, which in turn increases CDT2 transcription, whereas E6-mediated p53 degradation downregulates TRIM22, a novel E3 ligase for CDT2 degradation, leading to CDT2 accumulation to promote growth and survival of cervical cancer cells. Importantly, CDT2 depletion induces DNA aneuploidy and senescence via stabilization of histone lysine methyltransferase SET8, a CRL4^CDT2 substrate, acting as a tumor suppressor. Collectively, the TRIM22-CDT2-SET8 axis is the key mediator of the p53/Rb signals in regulation of growth and survival of HPV-positive cervical carcinoma cells, Thus, CDT2 could serve as a prognostic biomarker and therapeutic target for these carcinomas.

持续感染高危人乳头瘤病毒（HPV）是宫颈癌发展的主要因素。虽然HPV癌蛋白E6和E7通过灭活p53和Rb途径明显触发宫颈肿瘤发生，但p53/Rb灭活的下游介质仍不清楚。在这里，我们报道CDT2， Cullin-RING连接酶4 （CRL4）的一个亚基，在宫颈癌组织中显著上调，这与E6/E7的表达和较差的患者生存有关。从机制上讲，e7介导的Rb降解上调E2F1，从而增加CDT2转录，而e6介导的p53降解下调TRIM22，一种新的CDT2降解E3连接酶，导致CDT2积累，促进宫颈癌细胞的生长和存活。重要的是，CDT2缺失通过稳定组蛋白赖氨酸甲基转移酶SET8（一种CRL4CDT2底物，作为肿瘤抑制因子）诱导DNA非整倍体和衰老。综上所述，TRIM22-CDT2-SET8轴是p53/Rb信号调控hpv阳性宫颈癌细胞生长和存活的关键介质，因此，CDT2可以作为这些癌的预后生物标志物和治疗靶点。

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引用次数: 0

Comparative effects of combustible cigarette versus electronic cigarette exposures on KRAS mutant lung cancer promotion 可燃香烟与电子烟暴露对KRAS突变肺癌促进的比较影响

IF 4.8 2区医学 Q1 Biochemistry, Genetics and Molecular Biology

Neoplasia

Pub Date : 2025-09-01 Epub Date: 2025-06-13 DOI: 10.1016/j.neo.2025.101185

Walter V. Velasco , Maria T. Grimaldo , Nastaran Karimi , Michael J. Clowers , Avantika Krishna , Ranran Wu , Rahmah Ejaz , Bo Yuan , Segundo del Aguila , Iman Bouchelkia , Javier Eduardo Moreno Barragan , Katherine E. Larsen , Yasmina Rezai , Farbod Khalaj , Kyler Mitra , Carlos Reyna Rodriguez , Ricardo Millares , Angelica Baca de Anda , Susana Castro-Pando , Umesh C. Karandikar , Seyed Javad Moghaddam

Despite the emerging public health concern related to the use of electronic cigarette vapors (ECV), its impact on lung cancer is poorly understood. We assessed the effect of ECV on lung tumorigenesis in a mouse model of lung adenocarcinoma. Mice were exposed to either room air, combustible cigarette smoke (CCS), or ECV 2 hours daily for 8 weeks at which lung samples were harvested and studied for different outcomes. We found that CCS, but not ECV, led to a significant increase in tumor burden. Immunophenotyping of both CCS- and ECV-exposed lungs displayed pronounced pro-tumor immunosuppressive phenotypes, characterized by significantly decreased CD4+ IFNγ+ and CD8+ GZMB+ T cells along with an elevated CD4+ FOXP3+ regulatory T cells. However, differential changes in myeloid cells were observed between CCS and ECV-exposed lungs. A microbiome profiling of matched stool and lung samples showed differences in the relative abundance of lung Pseudomonadotas, while gut Bacillota, particularly Turicibacter, and Ileibacterium were increased by CCS and ECV. We conclude that both CCS and ECV exposure under the applied regimen lead to a protumor immune suppressive lung microenvironment although with different magnitudes and slightly different phenotypes that might explain their differential effects on tumor burden warranting further studies.

尽管与使用电子烟蒸汽（ECV）有关的公共卫生问题正在出现，但人们对其对肺癌的影响知之甚少。我们在肺腺癌小鼠模型中评估了ECV对肺肿瘤发生的影响。小鼠每天暴露于室内空气、可燃香烟烟雾（CCS）或ECV中2小时，持续8周，在此期间采集肺样本并研究不同的结果。我们发现，CCS，而不是ECV，导致肿瘤负荷显著增加。CCS-和ecv暴露肺的免疫表型均显示出明显的促肿瘤免疫抑制表型，其特征是CD4+ IFNγ+和CD8+ GZMB+ T细胞显著减少，CD4+ FOXP3+调节性T细胞升高。然而，在CCS和ecv暴露的肺中观察到骨髓细胞的不同变化。匹配的粪便和肺部样本的微生物组分析显示，肺部假单胞菌的相对丰度存在差异，而肠道芽孢杆菌，特别是Turicibacter和回肠杆菌，则因CCS和ECV而增加。我们得出结论，在应用方案下，CCS和ECV暴露都导致了肿瘤免疫抑制的肺微环境，尽管其程度不同，表型略有不同，这可能解释了它们对肿瘤负荷的不同影响，值得进一步研究。

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引用次数: 0

The immune response against cancer is modulated by stromal cell fibronectin 对癌症的免疫反应是由基质细胞纤维连接蛋白调节的

IF 4.8 2区医学 Q1 Biochemistry, Genetics and Molecular Biology

Neoplasia

Pub Date : 2025-09-01 Epub Date: 2025-06-30 DOI: 10.1016/j.neo.2025.101196

Alexander Lubosch , Lauren Pitt , Caren Zoeller , Franziska Wirth , Tarik Exner , Barbara Steigenberger , Guido Wabnitz , Jutta Schroeder-Braunstein , Inaam A. Nakchbandi

Cancer-associated fibroblasts remain poorly understood, with some of them originating from the bone marrow. We therefore took advantage of the diversity of bone marrow stromal cells to shed light on how fibroblasts modulate cancer growth.

In two murine cancer models, adding these fibroblasts to tumor cells resulted in smaller lesions. Suppression was enhanced by pretreatment with fibronectin, while genetic deletion of fibronectin in a small subpopulation of stromal cells expressing osterix/sp7 restored growth. The suppressive stromal population showed two more characteristics: the absence of CD31/pecam1 and CD105/endoglin. However, only a decrease in CD105/ENDOGLIN in melanoma patients translated in improved survival. Mechanistically, fibronectin or fibronectin fragments activate integrin α5β1 and TLR4 and increase chemokine production by stromal cells ultimately leading to enhanced recruitment and activity of Ly6G⁺ myeloid cells without T-cell involvement.

This work thus characterizes a beneficial interaction between stromal cells and neutrophils enhancing the immune response against early cancer.

与癌症相关的成纤维细胞仍然知之甚少，其中一些来自骨髓。因此，我们利用骨髓基质细胞的多样性来阐明成纤维细胞如何调节癌症的生长。在两种小鼠癌症模型中，将这些成纤维细胞添加到肿瘤细胞中导致较小的病变。纤维连接蛋白预处理增强了抑制作用，而在一小部分表达osterix/sp7的基质细胞亚群中，纤维连接蛋白的基因缺失恢复了生长。抑制性间质群体表现出另外两个特征：缺乏CD31/pecam1和CD105/endoglin。然而，在黑色素瘤患者中，只有CD105/ENDOGLIN的降低转化为生存率的提高。从机制上讲，纤维连接蛋白或纤维连接蛋白片段激活整合素α5β1和TLR4，并增加基质细胞的趋化因子产生，最终导致Ly6G+骨髓细胞的募集和活性增强，而不涉及t细胞。因此，这项工作表征了基质细胞和中性粒细胞之间有益的相互作用，增强了对早期癌症的免疫反应。

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引用次数: 0

Cancer-associated VEGFR2R1032Q sustains receptor activation also by promoting ligand-independent hetero-dimerization with co-expressed wild-type VEGFR2 and translocation into lipid rafts 癌症相关的VEGFR2R1032Q也通过促进与共表达的野生型VEGFR2不依赖配体的异二聚化和转运到脂质筏中来维持受体激活

IF 4.8 2区医学 Q1 Biochemistry, Genetics and Molecular Biology

Neoplasia

Pub Date : 2025-09-01 Epub Date: 2025-06-14 DOI: 10.1016/j.neo.2025.101195

Cosetta Ravelli , Michela Corsini , Roberto Bresciani , Angela M. Rizzo , Luca Zammataro , Paola A. Corsetto , Elisabetta Grillo , Stefania Mitola

The substitution R1032Q is the most frequent non-synonymous mutation of the vascular endothelial growth factor receptor 2 (VEGFR2) in cancer patients, classified as a loss-of-function variant. Here we characterize the molecular bases of its role in cancer, demonstrating that it lacks significant activity and pro-oncogenic effects in VEGFR2-negative tumor cells, while being able to sustain the tumorigenic potential of VEGFR2-positive cancer cells. By implementing a cell model that allows expression of either VEGFR2^R1032Q alone or in combination with VEGFR2^WT, we showed that the effects of mutated VEGFR2 are at least in part due to the ability of VEGFR2^R1032Q to form functional heterodimers with co-expressed VEGFR2^WT that result in increased kinase activity and receptor phosphorylation. This was associated with reduced mobility of the receptor on the membrane, linked to its translocation into detergent-resistant membrane (DRM) domains (e.g. lipid rafts), which showed alterations in lipid compositions and structure. These data shed light on a novel oncogenic mechanism of activation of VEGFR2, clarifying the paradoxical loss-of-function nature of the substitution R1032Q of VEGFR2.

替代R1032Q是癌症患者中血管内皮生长因子受体2 （VEGFR2）最常见的非同义突变，被归类为功能丧失变体。在这里，我们描述了其在癌症中作用的分子基础，证明它在vegfr2阴性肿瘤细胞中缺乏显著的活性和促癌作用，同时能够维持vegfr2阳性癌细胞的致瘤潜力。通过建立一个允许单独表达VEGFR2R1032Q或与VEGFR2WT联合表达的细胞模型，我们发现突变的VEGFR2的作用至少部分是由于VEGFR2R1032Q与共表达的VEGFR2WT形成功能性异源二聚体的能力，从而导致激酶活性和受体磷酸化增加。这与膜上受体的移动性降低有关，与其易位到耐洗涤剂膜（DRM）结构域（如脂筏）有关，这显示了脂质成分和结构的改变。这些数据揭示了VEGFR2激活的一种新的致癌机制，阐明了VEGFR2替代基因R1032Q的自相矛盾的功能丧失性质。

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引用次数: 0