Translational Oncology最新文献_第2页

Diagnostic efficacy of blood biomarkers for differentiating early-stage pancreatic cancer from chronic pancreatitis: A systematic review and network meta-analysis 血液生物标志物鉴别早期胰腺癌和慢性胰腺炎的诊断效果：系统综述和网络荟萃分析

IF 5 2区医学 Q2 Medicine

Translational Oncology

Pub Date : 2026-01-16 DOI: 10.1016/j.tranon.2026.102674

Di Wu , Zeng-Kan Du , Yuan-Chen Wang , Yi-Zhou Zheng , Hang-Ming Qi , Yu-Ru-Chen Zhu , Yu Cao , Lei Wang , Wen-Bin Zou , Zhuan Liao

Background

Early diagnosis of pancreatic cancer (PC) remains challenging, particularly in patients with chronic pancreatitis (CP). Currently, imaging is often inaccurate and biopsy is inherently invasive. This is the first network meta-analysis (NMA) comparing blood-based biomarkers for differentiating PC from CP.

Methods

PubMed and EMBASE were searched for studies evaluating blood-based biomarkers for distinguishing PC from CP. Risk of bias was assessed with QUADAS-2. We conducted individual biomarker meta-analysis with generalized bivariate models. For the NMA, we applied a Bayesian inference approach via a Markov-chain Monte Carlo random effects model. The surface under the cumulative ranking curve was used to rank the diagnostic performance of the biomarkers.

Results

Across 139 enrolled studies, 49 biomarkers or panels were analyzed. For differentiating PC from CP, tumor polypeptide antigen (TPA) had the highest area under the summary receiver operating characteristic curve (AUSROC) (0.92). The NMA revealed that microRNA-196b (miR-196b) ranked highest in sensitivity (OR 3.74e+27), while the combination of carbohydrate antigen 19–9 (CA199) and a panel of eight extracellular vesicle long RNAs (exLRs) exhibited the highest specificity (OR 3.78). For early-stage (stage I and II) PC, the eight exLRs showed the highest relative sensitivity (OR 7.00), and carcinoembryonic antigen (CEA) demonstrated the highest specificity (OR 4.70).

Conclusion

CA199 demonstrated only moderate diagnostic discrimination between PC and CP, with reduced efficacy in early-stage PC. Combining CA199 and eight exLRs exhibited promising differential diagnostic efficacy with both high sensitivity and specificity.

背景胰腺癌（PC）的诊断仍然具有挑战性，特别是慢性胰腺炎（CP）患者。目前，成像通常是不准确的，活检本身就是侵入性的。方法检索spubmed和EMBASE中评估血液生物标志物区分PC和CP的研究，并使用QUADAS-2评估偏倚风险。我们使用广义双变量模型进行了个体生物标志物荟萃分析。对于NMA，我们通过马尔可夫链蒙特卡洛随机效应模型应用贝叶斯推理方法。累积排序曲线下的曲面用于对生物标志物的诊断性能进行排序。结果在139项入组研究中，分析了49种生物标志物或组。在鉴别PC与CP时，肿瘤多肽抗原（tumor polypeptide antigen， TPA）在总接受者工作特征曲线（AUSROC）下的面积最高（0.92）。NMA显示，microRNA-196b （miR-196b）的敏感性最高（OR 3.74e+27），而碳水化合物抗原19-9 （CA199）和一组8个细胞外囊泡长rna （exlr）的组合具有最高的特异性（OR 3.78）。对于早期（I期和II期）PC， 8个exlr的相对敏感性最高（OR 7.00），癌胚抗原（CEA）的特异性最高（OR 4.70）。结论ca199对PC和CP的诊断鉴别能力较弱，对早期PC的鉴别能力较弱。CA199联合8种exLRs具有较高的敏感性和特异性，具有良好的鉴别诊断效果。

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引用次数: 0

Obesity and cancer: Relevance of DNA damage response 肥胖和癌症：DNA损伤反应的相关性

IF 5 2区医学 Q2 Medicine

Translational Oncology

Pub Date : 2026-01-15 DOI: 10.1016/j.tranon.2025.102657

Bhavana Deshmukh , Amrendra Kumar Ajay , Manoj Kumar Bhat

Obesity is a non-communicable, multifactorial disorder that has steadily emerged as one of the major global health concerns. It significantly increases the risk of diabetes, cardiovascular diseases and cancer. In obesity, the accumulation of excess fat causes increase in the circulatory levels of adipose tissue-specific hormones (adipokines) and exacerbates carbohydrate-fuelled metabolic stress. These factors promote oxidative and genotoxic stress, resulting in chronic inflammation. Moreover, obesity-related factors contribute to increase in DNA damage and disrupt the DNA Damage Response (DDR), thereby promoting genomic instability. Consequently, obesity may facilitate a complex, multi-step process of cellular transformation and cancer progression. However, the mechanisms linking obesity-associated DDR alterations to cancer progression are active areas of investigation. Therefore, elucidating these aspects of DDR in obesity could enhance our understanding of the risk assessment and facilitate advancement in treatment strategies for patients with cancers and obesity.

肥胖是一种非传染性、多因素疾病，已逐渐成为全球主要健康问题之一。它大大增加了患糖尿病、心血管疾病和癌症的风险。在肥胖中，过量脂肪的积累导致脂肪组织特异性激素（脂肪因子）循环水平的增加，并加剧碳水化合物驱动的代谢压力。这些因素促进氧化应激和基因毒性应激，导致慢性炎症。此外，肥胖相关因素导致DNA损伤增加，破坏DNA损伤反应（DDR），从而促进基因组不稳定。因此，肥胖可能促进了一个复杂的、多步骤的细胞转化和癌症进展过程。然而，将肥胖相关的DDR改变与癌症进展联系起来的机制是研究的活跃领域。因此，阐明肥胖中DDR的这些方面可以增强我们对风险评估的理解，促进癌症和肥胖患者治疗策略的进步。

引用次数: 0

NEIL1 suppresses ROS accumulation to promote temozolomide resistance and malignant progression in glioma cells NEIL1抑制ROS积累，促进替莫唑胺耐药和胶质瘤细胞恶性进展

IF 5 2区医学 Q2 Medicine

Translational Oncology

Pub Date : 2026-01-13 DOI: 10.1016/j.tranon.2026.102667

Shuo Li , Chenhao Fang , Qingyue Yuan , Xianzhen Chen

Background

Glioma is the most common malignant primary brain tumor. Temozolomide (TMZ) is the standard first-line chemotherapy, but its efficacy is severely limited by acquired resistance. Understanding resistance mechanisms, especially beyond traditional DNA repair, is crucial for improving outcomes.

Methods

We integrated multi-database glioma transcriptomics (TCGA, GTEx, CGGA). Bioinformatics (differential expression, WGCNA, glycolipid metabolism gene screening) and machine learning (LASSO, random forest) identified key genes, focusing on the DNA glycosylase NEIL1. Its expression was assessed in U251 MG cells versus TMZ-resistant (U251 MG/TMZ) cells. Gain/loss-of-function studies (lentiviral knockdown/overexpression) and pharmacological inhibition (a 2-thioxanthine derivative, TX16) were used to evaluate NEIL1′s role in proliferation (CCK-8, EdU), migration, invasion, apoptosis (TUNEL), ROS, and TMZ sensitivity (IC50). A subcutaneous nude mouse model provided in vivo validation.

Results

NEIL1 was aberrantly expressed in glioma and enriched in PI3K-Akt/cAMP signaling, suggesting that it may promote the malignant behavior of U251 MG cells through these pathways. Its expression was significantly higher in TMZ-resistant cells (P < 0.001). NEIL1 overexpression promoted malignant phenotypes (proliferation, migration, invasion, P < 0.05), while its knockdown suppressed them. Critically, NEIL1 overexpression attenuated TMZ-induced ROS and DNA damage, increased cell viability and IC₅₀ (1.2-fold), and bolstered TMZ resistance. The NEIL1 inhibitor TX16 reversed these malignant behaviors and restored TMZ sensitivity (P < 0.05), reinstating ROS-driven apoptosis. In vivo, NEIL1 promoted tumor growth, which was suppressed by TX16.

Conclusion

NEIL1 drives glioma malignancy and TMZ resistance by mitigating oxidative stress and DNA damage, highlighting its role as a promising target to overcome chemoresistance.

神经胶质瘤是最常见的原发性恶性脑肿瘤。替莫唑胺（TMZ）是标准的一线化疗药物，但其疗效受到获得性耐药的严重限制。了解耐药性机制，尤其是传统DNA修复机制之外的机制，对于改善治疗效果至关重要。方法整合多数据库胶质瘤转录组学（TCGA, GTEx， CGGA）。生物信息学（差异表达，WGCNA，糖脂代谢基因筛选）和机器学习（LASSO，随机森林）鉴定了关键基因，重点是DNA糖基化酶NEIL1。比较其在U251 MG细胞和TMZ耐药（U251 MG/TMZ）细胞中的表达。通过获得/丧失功能研究（慢病毒敲除/过表达）和药理学抑制（2-硫黄嘌呤衍生物TX16）来评估NEIL1在增殖（CCK-8, EdU）、迁移、侵袭、凋亡（TUNEL）、ROS和TMZ敏感性（IC50）中的作用。皮下裸鼠模型提供了体内验证。结果neil1在胶质瘤中异常表达，并在PI3K-Akt/cAMP信号通路中富集，提示其可能通过这些通路促进U251 MG细胞的恶性行为。其在tmz耐药细胞中的表达显著升高（P < 0.001）。NEIL1过表达促进恶性表型（增殖、迁移、侵袭，P < 0.05），而其敲低抑制这些表型。重要的是，NEIL1过表达减弱了TMZ诱导的ROS和DNA损伤，增加了细胞活力和IC50（1.2倍），并增强了TMZ抗性。NEIL1抑制剂TX16逆转了这些恶性行为，恢复了TMZ敏感性（P < 0.05），恢复了ros驱动的细胞凋亡。在体内，NEIL1促进肿瘤生长，而TX16抑制NEIL1的生长。结论neil1通过减轻氧化应激和DNA损伤驱动胶质瘤恶性和TMZ耐药，是克服化疗耐药的有希望的靶点。

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引用次数: 0

Spatial and single-cell multi-omics reveal pro-angiogenic THY1⁺ fibroblast subtypes predicting prognosis in prostate cancer 空间和单细胞多组学揭示促血管生成THY1 +成纤维细胞亚型预测前列腺癌预后

IF 5 2区医学 Q2 Medicine

Translational Oncology

Pub Date : 2026-01-12 DOI: 10.1016/j.tranon.2026.102664

Yongqiang Huang , Chunping Xiang , Yu Wang , Wei Zhang , Leilei Du , Wenfeng Wang , Guohai Shi , Jianhua Wang

Background

Cancer-associated fibroblasts (CAFs) play a key role in prostate cancer (PCa) progression, though their heterogeneity and specific protumorigenic subsets remain poorly characterized. This study aimed to identify and validate a distinct THY1⁺ CAF subset associated with aggressive PCa.

Methods

Multiomics data from public (TCGA-PRAD, GEO) and prospective (FUSCC, n = 84) cohorts were analyzed. An 8-gene CAF-derived prognostic signature was constructed using LASSO Cox regression. THY1⁺ CAF clusters were identified via scRNA-seq. Primary CAFs were isolated from patient tissues, and THY1⁺/THY1⁻ subpopulations were purified via MACS/FACS. Angiogenic function and secretory profiles were assessed through tube formation assays, ELISA, and antibody arrays. THY1 knockdown and CXCR2 inhibition were used for mechanistic studies. Clinical relevance was evaluated via qPCR and multiplex immunohistochemistry on tissue microarrays.

Results

High CAF abundance correlated with aggressive clinicopathological features and poor prognosis in PCa. The 8-gene signature effectively predicted biochemical recurrence (BCR). scRNA-seq revealed THY1⁺ CAFs as a proangiogenic subpopulation. THY1⁺ CAFs enhanced angiogenesis via increased secretion of CXCL6 and VEGFA. CXCL6 promoted endothelial tube formation through CXCR2 activation, while THY1 knockdown downregulated VEGFA and impaired angiogenesis. High THY1⁺ CAF infiltration was associated with significantly worse recurrence-free survival.

Conclusion

THY1⁺ CAFs represent a proangiogenic subset that drives PCa progression via the CXCL6/CXCR2 axis and THY1-mediated VEGFA expression. These findings highlight stromal THY1 and the CXCL6/CXCR2 pathway as potential therapeutic targets.

背景：癌症相关成纤维细胞（CAFs）在前列腺癌（PCa）的进展中起着关键作用，尽管它们的异质性和特定的蛋白发生亚群仍然缺乏特征。这项研究旨在鉴定和验证与侵袭性PCa相关的THY1 + CAF亚群。方法：对来自公共队列（TCGA-PRAD， GEO）和前瞻性队列（FUSCC, n = 84）的多组学数据进行分析。使用LASSO - Cox回归构建8基因caf衍生的预后特征。通过scRNA-seq鉴定THY1 + CAF簇。从患者组织中分离出原代CAFs，通过MACS/FACS纯化THY1⁺/THY1⁻亚群。血管生成功能和分泌谱通过管形成试验、ELISA和抗体阵列进行评估。THY1敲除和CXCR2抑制用于机制研究。通过组织微阵列上的qPCR和多重免疫组化来评估临床相关性。结果：高CAF丰度与前列腺癌侵袭性临床病理特征和不良预后相关。8基因标记可有效预测生化复发（BCR）。scRNA-seq显示THY1 + CAFs是促血管生成亚群。THY1 + CAFs通过增加CXCL6和VEGFA的分泌增强血管生成。CXCL6通过激活CXCR2促进内皮管的形成，而THY1敲低则下调VEGFA并损害血管生成。高THY1 + CAF浸润与明显较差的无复发生存率相关。结论：THY1 + CAFs代表一个促血管生成亚群，通过CXCL6/CXCR2轴和THY1介导的VEGFA表达驱动PCa进展。这些发现强调基质THY1和CXCL6/CXCR2通路是潜在的治疗靶点。

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引用次数: 0

CTSB-positive tumor-associated macrophages shape prognosis and therapeutic response in lung adenocarcinoma ctsb阳性肿瘤相关巨噬细胞影响肺腺癌的预后和治疗反应

IF 5 2区医学 Q2 Medicine

Translational Oncology

Pub Date : 2026-01-12 DOI: 10.1016/j.tranon.2026.102671

Caiqiang Zhu , Liang Liang , Ning Xue , Dan Mei , Meng Tian , Zhaoyue Zhang , Xinchen Sun , Xiaofeng Ding

Background

Lung adenocarcinoma (LUAD) remains a major clinical challenge in assessment of clinical outcomes and therapeutic response. Although tumor-associated macrophages (TAMs) are known as crucial regulators of tumor progression, their heterogeneity and prognostic relevance in LUAD have not been fully elucidated.

Methods

The heterogeneity of TAMs was detected by integration analyses of single-cell data and spatial transcriptome data. The CTSB⁺ TAM-related signature (CTRS) was developed by machine learning algorithms across four LUAD datasets. Multi-omics analysis and functional experiments were applied to uncover the potential role and mechanism of CTSB⁺ TAMs in LUAD.

Results

Single-cell analysis identified CTSB⁺ TAM as a crucial player in LUAD progression with poor prognosis. The spatial co-localization of CTSB⁺ TAMs and tumor cells was confirmed on LUAD slides. Our proposed CTRS was generated and validated in four independent LUAD cohorts, with high scores indicating unfavorable outcomes Furthermore, high CTRS scores were correlated with immunosuppressive status, and poor responses to immune checkpoint blockade. Functional experiments demonstrated the role of CTSB⁺ TAMs in boosting proliferation and migration in LUAD cells.

Conclusion

Our research develops CTRS with reliable performance in evaluating patient clinical outcomes in LUAD, highlighting its potential utility in clinical decision-making.

背景肺腺癌（LUAD）仍然是评估临床结果和治疗反应的主要临床挑战。尽管肿瘤相关巨噬细胞（tam）被认为是肿瘤进展的关键调节因子，但它们在LUAD中的异质性和预后相关性尚未完全阐明。方法通过对单细胞数据和空间转录组数据的整合分析，检测tam的异质性。CTSB+ tam相关签名（CTRS）是通过跨四个LUAD数据集的机器学习算法开发的。通过多组学分析和功能实验，揭示了CTSB+ tam在LUAD中的潜在作用和机制。结果单细胞分析发现CTSB + TAM在预后不良的LUAD进展中起关键作用。LUAD玻片证实了CTSB + tam与肿瘤细胞的空间共定位。我们提出的CTRS在四个独立的LUAD队列中生成并验证，得分高表明结果不利。此外，高CTRS得分与免疫抑制状态和免疫检查点封锁反应差相关。功能实验证实了CTSB+ tam在LUAD细胞中促进增殖和迁移的作用。结论本研究开发的CTRS在评估LUAD患者临床结果方面具有可靠的性能，突出了其在临床决策中的潜在应用价值。

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引用次数: 0

Advances on drug therapy for KRASG12C-mutant non-small-cell lung cancer krasg12c突变体非小细胞肺癌的药物治疗进展

IF 5 2区医学 Q2 Medicine

Translational Oncology

Pub Date : 2026-01-12 DOI: 10.1016/j.tranon.2026.102668

Ting Tian, Wangping Li

Lung cancer has an extremely high mortality rate among malignant tumors, posing a significant threat to human health Among all lung cancer cases, non-small cell lung cancer (NSCLC) accounts for a significant proportion and has become a hot topic in clinical research and treatment. The Kirsten rat sarcoma viral oncogene homolog (KRAS) is one of the most common oncogenic drivers in NSCLC, closely associated with tumor initiation, treatment response, and prognosis. However, due to the relatively smooth surface of the KRAS protein and the lack of drug-binding pockets, it has long been regarded as an "undrugable target". With further research, recently, targeted drugs targeting the KRAS^G12C gene mutation have achieved significant breakthroughs in clinical trials, especially the application of KRAS^G12C-specific inhibitors adagrasib and sotorasib, which has changed the treatment landscape for NSCLC patients. To address challenges such as tumor heterogeneity, the complexity of the tumor microenvironment, interpatient variability, and acquired drug resistance mechanisms, combination therapy strategies involving KRAS^G12C inhibitors have emerged sequentially. This article systematically reviews the progress of targeted therapy for KRAS^G12C-mutant NSCLC and the results of related clinical trials, while exploring novel therapeutic strategies for patients with KRAS^G12C mutations, aiming to provide a reference for the selection of clinical treatment regimens.

肺癌是恶性肿瘤中死亡率极高的肿瘤，对人类健康构成重大威胁。在所有肺癌病例中，非小细胞肺癌（non-small cell Lung cancer， NSCLC）占了相当大的比例，已成为临床研究和治疗的热点。Kirsten大鼠肉瘤病毒癌基因同源物（KRAS）是NSCLC中最常见的致癌驱动因子之一，与肿瘤起始、治疗反应和预后密切相关。然而，由于KRAS蛋白表面相对光滑，缺乏药物结合口袋，长期以来被认为是“不可磨灭的靶标”。随着研究的深入，近年来，针对KRASG12C基因突变的靶向药物在临床试验中取得了重大突破，尤其是KRASG12C特异性抑制剂阿达格拉西和索托拉西的应用，改变了NSCLC患者的治疗格局。为了应对诸如肿瘤异质性、肿瘤微环境复杂性、患者间变异性和获得性耐药机制等挑战，涉及KRASG12C抑制剂的联合治疗策略相继出现。本文系统综述KRASG12C突变型NSCLC靶向治疗进展及相关临床试验结果，同时探索KRASG12C突变患者的新治疗策略，旨在为临床治疗方案的选择提供参考。

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引用次数: 0

Mechanistic and translational insights into plant-derived natural products in preclinical multiple myeloma research: Current evidence 临床前多发性骨髓瘤研究中植物来源的天然产物的机制和转化见解：目前的证据

IF 5 2区医学 Q2 Medicine

Translational Oncology

Pub Date : 2026-01-08 DOI: 10.1016/j.tranon.2026.102666

Lulu Li , Jie Xu , Liming Yu , Jingbo Shi , Changnian Li , Jiabao Gu , Yaru Wang , Siyuan Cui

Multiple myeloma (MM) is a hematological malignancy characterized by the clonal proliferation of abnormal plasma cells, with marked heterogeneity and therapeutic refractoriness. Despite the introduction of proteasome inhibitors (PIs), immunomodulatory drugs (IMiDs), monoclonal antibodies (mAbs), and chimeric antigen receptor T-cell (CAR-T) therapy, relapse and drug resistance remain major challenges that urgently need to be addressed. Plant-derived natural products have attracted increasing attention in recent years due to their multi-target synergistic effects, demonstrating unique potential in inducing MM cell apoptosis, reversing drug resistance, and modulating the immune microenvironment—making them a rising focus in translational medicine research. In this structured narrative review, we systematically summarize the anti-myeloma mechanisms of fourteen plant-derived natural products, including plant-derived monomeric compounds (baicalein, artemisinin, curcumin, celastrol, gambogic acid, resveratrol, ginsenosides, icariin, oridonin, plumbagin, formononetin) and standardized plant extracts (Strychnos nux-vomica root extract, dandelion flavonoids, Hedyotis diffusa polysaccharides). This review highlights their multi-target regulatory effects on signaling pathways, cell cycle modulation, and immune regulation, and further discusses their potential translational value in overcoming drug resistance and optimizing combination treatment strategies. Literature was retrieved from PubMed, Web of Science, and CNKI databases, covering studies published up to January 2025. Although plant-derived natural products exhibit promising multi-target regulatory mechanisms in MM therapy, their clinical translation remains limited by poor bioavailability of single compounds and the lack of standardized extracts. Future research should integrate systems pharmacology with clinical studies to elucidate multi-component synergistic networks and develop novel targeted formulations, thereby accelerating the efficient translation of phytochemicals from bench to bedside.

多发性骨髓瘤（MM）是一种以异常浆细胞克隆增生为特征的血液系统恶性肿瘤，具有明显的异质性和治疗难治性。尽管引入了蛋白酶体抑制剂（pi）、免疫调节药物（IMiDs）、单克隆抗体（mab）和嵌合抗原受体t细胞（CAR-T）治疗，但复发和耐药仍然是迫切需要解决的主要挑战。近年来，植物源性天然产物因其多靶点协同作用而受到越来越多的关注，在诱导MM细胞凋亡、逆转耐药、调节免疫微环境等方面显示出独特的潜力，成为转化医学研究的热点。在这篇结构化的叙述综述中，我们系统地总结了14种植物源性天然产物的抗骨髓瘤机制，包括植物源性单体化合物（黄芩素、青蒿素、姜黄素、celastrol、藤黄酸、白藜芦醇、人参皂苷、淫羊藿苷、冬凌草苷、白桦柄花素）和标准化植物提取物（马钱子根提取物、蒲公英黄酮、白花蛇耳草多糖）。本文综述了它们在信号通路、细胞周期调节和免疫调节等方面的多靶点调控作用，并进一步讨论了它们在克服耐药和优化联合治疗策略方面的潜在翻译价值。文献检索自PubMed、Web of Science和CNKI数据库，涵盖截至2025年1月发表的研究。尽管植物来源的天然产物在多发性骨髓瘤治疗中显示出有希望的多靶点调节机制，但它们的临床转化仍然受到单一化合物生物利用度差和缺乏标准化提取物的限制。未来的研究应将系统药理学与临床研究结合起来，阐明多组分协同网络，开发新的靶向制剂，从而加快植物化学物质从实验室到床边的有效转化。

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引用次数: 0

Tumor derived adiponectin induces immunosuppressive macrophages in upper tract urothelial carcinoma 肿瘤源性脂联素在上尿路上皮癌中诱导免疫抑制巨噬细胞。

IF 5 2区医学 Q2 Medicine

Translational Oncology

Pub Date : 2026-01-06 DOI: 10.1016/j.tranon.2025.102599

Cheng-Huang Shen , PiChe Chen , Chia-Bin Chang , Chih-Chia Chang , Meilin Wang , Lien-Ping Chou , Ya-Yan Lai , Ming-Yang Lee , Shu-Fen Wu

Upper tract urothelial carcinoma (UTUC) is a rare urologic cancer that is more aggressive and has a poorer survival rate compared to bladder cancer. Previously, we linked the UTUC derived factors with tumor-infiltrating immune cells. Macrophages are considered the most abundant immune cell population within tumors and serve as key regulators of the tumor microenvironment. This study aimed to investigate their role in modulating immunosuppression in UTUC tumors. Our results indicated that UTUC patients had higher proportion of M2-type macrophages in the periphery, and that tumor-infiltrating M2 macrophages were inversely correlated with tumor-infiltrating T lymphocytes within UTUC tumors. The supernatants from UTUC tumor tissue, as well as the predominant factor adiponectin, caused upregulation of arginase-1 and CD206 expression in THP-1 differentiated macrophages. Furthermore, macrophages treated with supernatants from UTUC tumor tissue or adiponectin alone inhibited CD4 T cell and CD8 T cell proliferation, along with reduction of effective cytokines produced by T cells. These results suggest that macrophages modulated by adiponectin are associated with T cell suppression in the UTUC tumor microenvironment, highlighting a potential therapeutic target.

上尿路上皮癌（UTUC）是一种罕见的泌尿系统癌症，与膀胱癌相比更具侵袭性，生存率较低。之前，我们将UTUC衍生因子与肿瘤浸润性免疫细胞联系起来。巨噬细胞被认为是肿瘤中最丰富的免疫细胞群，是肿瘤微环境的关键调节因子。本研究旨在探讨它们在调节UTUC肿瘤免疫抑制中的作用。我们的研究结果表明，UTUC患者外周血中M2型巨噬细胞比例较高，且UTUC肿瘤内浸润性M2巨噬细胞与浸润性T淋巴细胞呈负相关。UTUC肿瘤组织上清液及优势因子脂联素引起THP-1分化巨噬细胞精氨酸酶-1和CD206表达上调。此外，用UTUC肿瘤组织上清液或脂联素单独处理巨噬细胞可抑制CD4 T细胞和CD8 T细胞的增殖，并减少T细胞产生的有效细胞因子。这些结果表明，脂联素调节的巨噬细胞与UTUC肿瘤微环境中的T细胞抑制有关，突出了一个潜在的治疗靶点。

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引用次数: 0

First functional evidence that a rare germline TP53β variant drives senescence-associated immune suppression and impairs apoptosis and cell migration in breast cancer patients 在乳腺癌患者中，一种罕见的种系TP53β变异驱动衰老相关的免疫抑制并损害细胞凋亡和细胞迁移的第一个功能证据。

IF 5 2区医学 Q2 Medicine

Translational Oncology

Pub Date : 2026-01-06 DOI: 10.1016/j.tranon.2025.102616

Claudia Christowitz , Daniel W Olivier , Nicole van der Merwe , Maritha J Kotze , Anna-Mart Engelbrecht

Introduction

Pathology-supported genetic testing (PSGT), a personalized medicine framework established in South Africa, led to the identification of a rare germline tumour suppressor protein 53 (TP53) beta-isoform (β) variant (NM_001126114.3, c.1018A>G, p.N340D) in a family with the Li-Fraumeni-like syndrome. While protein modeling predicted structural alterations consistent with impaired function, its pathogenicity remained unclear.

Aim

To determine the functional impact of the TP53β N340D variant on cell proliferation, cell death, senescence, migration, and anti-tumour activity using a translational ex vivo model.

Methods

Peripheral blood mononuclear cells (PBMCs) were isolated from female controls and breast cancer patients, with or without the TP53β N340D variant. Lipopolysaccharide (LPS)- and phytohemagglutinin-L (PHA-L)-stimulated proliferation was evaluated by a water-soluble tetrazolium 1 (WST-1) assay. Doxorubicin (DXR)-induced cell death was assessed using a WST-1 assay, flow cytometry, and western blotting. A senescence-associated beta-galactosidase assay and western blotting determined senescence. Migration and anti-tumour activity were assessed using a Transwell assay and co-culturing PBMCs with BT-549 spheroids.

Results

The TP53β N340D variant impaired DXR-induced cell death (p < 0.001), supported by reduced late apoptosis and decreased CASP3 and PARP activation. TP53β N340D PBMCs exhibited increased senescence (p < 0.01), potentially contributing to chemoresistance. Reduced LPS- and PHA-L-stimulated proliferation was dependent on cancer status. The variant reduced PBMC migration (p < 0.01), suggesting altered immune recruitment. Although anti-tumour activity appeared reduced in TP53β N340D PBMCs, spheroid size remained unchanged.

Conclusions

This study provides supporting evidence for the pathogenicity of the TP53β N340D variant and highlights the importance of integrating functional genomics into PSGT to enhance medical decision-making.

病理学支持基因检测（PSGT）是南非建立的一种个性化医学框架，在一个li - fraumeni样综合征家庭中发现了一种罕见的种系肿瘤抑制蛋白53 (TP53) β -同型异构体（β）变异（NM_001126114.3, c.1018A>G, p.N340D）。虽然蛋白质模型预测结构改变与功能受损一致，但其致病性仍不清楚。目的：通过翻译离体模型确定TP53β N340D变异对细胞增殖、细胞死亡、衰老、迁移和抗肿瘤活性的功能影响。方法：从携带或不携带TP53β N340D变异的女性对照和乳腺癌患者中分离外周血单个核细胞（PBMCs）。脂多糖（LPS）和植物血凝素- l （PHA-L）刺激的增殖通过水溶性四氮唑1 （WST-1）试验进行评估。采用WST-1检测、流式细胞术和western blotting评估阿霉素（DXR）诱导的细胞死亡。衰老相关的-半乳糖苷酶测定和免疫印迹法测定衰老。通过Transwell实验和pbmc与BT-549球体共培养来评估迁移和抗肿瘤活性。结果：TP53β N340D变异体损害了dxr诱导的细胞死亡（p < 0.001），减少了晚期凋亡，降低了CASP3和PARP的激活。TP53β N340D pmcs衰老增加（p < 0.01），可能有助于化学耐药。LPS和pha - l刺激的增殖减少依赖于癌症状态。该变异降低了PBMC迁移（p < 0.01），提示免疫募集发生改变。虽然TP53β N340D pbmc的抗肿瘤活性降低，但球体大小保持不变。结论：本研究为TP53β N340D变异的致病性提供了支持证据，并强调了将功能基因组学整合到PSGT中以提高医疗决策的重要性。

{"title":"First functional evidence that a rare germline TP53β variant drives senescence-associated immune suppression and impairs apoptosis and cell migration in breast cancer patients","authors":"Claudia Christowitz , Daniel W Olivier , Nicole van der Merwe , Maritha J Kotze , Anna-Mart Engelbrecht","doi":"10.1016/j.tranon.2025.102616","DOIUrl":"10.1016/j.tranon.2025.102616","url":null,"abstract":"<div><h3>Introduction</h3><div>Pathology-supported genetic testing (PSGT), a personalized medicine framework established in South Africa, led to the identification of a rare germline <em>tumour suppressor protein 53</em> (<em>TP53</em>) beta-isoform (β) variant (NM_001126114.3, c.1018A><em>G</em>, p.N340D) in a family with the Li-Fraumeni-like syndrome. While protein modeling predicted structural alterations consistent with impaired function, its pathogenicity remained unclear.</div></div><div><h3>Aim</h3><div>To determine the functional impact of the <em>TP53</em>β N340D variant on cell proliferation, cell death, senescence, migration, and anti-tumour activity using a translational <em>ex vivo</em> model.</div></div><div><h3>Methods</h3><div>Peripheral blood mononuclear cells (PBMCs) were isolated from female controls and breast cancer patients, with or without the <em>TP53</em>β N340D variant. Lipopolysaccharide (LPS)- and phytohemagglutinin-L (PHA-L)-stimulated proliferation was evaluated by a water-soluble tetrazolium 1 (WST-1) assay. Doxorubicin (DXR)-induced cell death was assessed using a WST-1 assay, flow cytometry, and western blotting. A senescence-associated beta-galactosidase assay and western blotting determined senescence. Migration and anti-tumour activity were assessed using a Transwell assay and co-culturing PBMCs with BT-549 spheroids.</div></div><div><h3>Results</h3><div>The <em>TP53</em>β N340D variant impaired DXR-induced cell death (<em>p</em> < 0.001), supported by reduced late apoptosis and decreased CASP3 and PARP activation. <em>TP53</em>β N340D PBMCs exhibited increased senescence (<em>p</em> < 0.01), potentially contributing to chemoresistance. Reduced LPS- and PHA-L-stimulated proliferation was dependent on cancer status. The variant reduced PBMC migration (<em>p</em> < 0.01), suggesting altered immune recruitment. Although anti-tumour activity appeared reduced in <em>TP53</em>β N340D PBMCs, spheroid size remained unchanged.</div></div><div><h3>Conclusions</h3><div>This study provides supporting evidence for the pathogenicity of the <em>TP53</em>β N340D variant and highlights the importance of integrating functional genomics into PSGT to enhance medical decision-making.</div></div>","PeriodicalId":48975,"journal":{"name":"Translational Oncology","volume":"64 ","pages":"Article 102616"},"PeriodicalIF":5.0,"publicationDate":"2026-01-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145913252","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"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

AVIL promotes osteosarcoma progression and cisplatin resistance via ARP2/3-mediated DNA damage repair AVIL通过arp2 /3介导的DNA损伤修复促进骨肉瘤进展和顺铂耐药。

IF 5 2区医学 Q2 Medicine

Translational Oncology

Pub Date : 2026-01-06 DOI: 10.1016/j.tranon.2025.102654

Zhenyi Chen , Guozhu Tang , Xuan Lv , Guoqing Ding, Mingyang Huang, Zhe Chen, Shuo Dai, Huilin Liu, Sheng Zhang, Lin Cai

Osteosarcoma (OS) is the most common primary malignant tumor of bone that commonly occurs in adolescents with poor prognosis. Neoadjuvant chemotherapy with the MAP regimen (high-dose methotrexate (Methotrexate), doxorubicin, and cisplatin) is essential for the standardized OS therapeutic, the good response of which critically exceeds the patient survival. However, approximately 30–40 % of patients develop chemoresistance, leading to metastatic disease or recurrence. Understanding the molecular mechanisms underlying chemoresistance is crucial for improving clinical outcomes. In this study, AVIL was identified as a key gene correlated with OS progression and chemoresistance. AVIL overexpression was found to promote OS progression in vitro and in vivo by enhancing cell proliferation, migration, and invasion, while AVIL deficiency exerted the inverse phenotypes. In vivo experiments further confirmed that AVIL overexpression promotes tumor growth and suppresses apoptosis. Mechanistically, AVIL interacts with the ARP2/3 complex, a key regulator of DNA damage repair via actin polymerization and cytoskeletal dynamics. This interaction was confirmed to facilitate cisplatin resistance, with reduced DNA damage response and increased cell survival caused by AVIL overexpression. Furthermore, using patient-derived organoid (PDO) models, we demonstrated that CK666, an ARP2/3 inhibitor, enhanced the chemotherapy efficacy of cisplatin by increasing DNA damage response and reversing AVIL-mediated cisplatin resistance. These findings highlight AVIL as a potential therapeutic target and suggest that targeting the AVIL-ARP2/3 axis could serve as an alternative strategy to overcome chemoresistance during OS treatment.

骨肉瘤（Osteosarcoma， OS）是最常见的原发性骨恶性肿瘤，常见于青少年，预后较差。MAP方案（高剂量甲氨蝶呤、阿霉素和顺铂）的新辅助化疗对于标准化的OS治疗至关重要，其良好的反应严重超过了患者的生存期。然而，大约30- 40%的患者出现化疗耐药，导致转移性疾病或复发。了解化疗耐药的分子机制对改善临床结果至关重要。在本研究中，AVIL被确定为与OS进展和化疗耐药相关的关键基因。研究发现，在体外和体内，AVIL过表达可以通过增强细胞增殖、迁移和侵袭来促进OS的进展，而AVIL缺乏则会产生相反的表型。体内实验进一步证实，AVIL过表达可促进肿瘤生长，抑制细胞凋亡。在机制上，AVIL与ARP2/3复合物相互作用，ARP2/3复合物是通过肌动蛋白聚合和细胞骨架动力学进行DNA损伤修复的关键调节因子。这种相互作用被证实促进顺铂耐药，降低DNA损伤反应，增加AVIL过表达引起的细胞存活率。此外，通过患者源性类器官（PDO）模型，我们证明了ARP2/3抑制剂CK666通过增加DNA损伤反应和逆转avil介导的顺铂耐药来增强顺铂的化疗疗效。这些发现强调了AVIL作为一个潜在的治疗靶点，并表明靶向AVIL- arp2 /3轴可以作为在OS治疗期间克服化疗耐药的替代策略。

{"title":"AVIL promotes osteosarcoma progression and cisplatin resistance via ARP2/3-mediated DNA damage repair","authors":"Zhenyi Chen , Guozhu Tang , Xuan Lv , Guoqing Ding, Mingyang Huang, Zhe Chen, Shuo Dai, Huilin Liu, Sheng Zhang, Lin Cai","doi":"10.1016/j.tranon.2025.102654","DOIUrl":"10.1016/j.tranon.2025.102654","url":null,"abstract":"<div><div>Osteosarcoma (OS) is the most common primary malignant tumor of bone that commonly occurs in adolescents with poor prognosis. Neoadjuvant chemotherapy with the MAP regimen (high-dose methotrexate (Methotrexate), doxorubicin, and cisplatin) is essential for the standardized OS therapeutic, the good response of which critically exceeds the patient survival. However, approximately 30–40 % of patients develop chemoresistance, leading to metastatic disease or recurrence. Understanding the molecular mechanisms underlying chemoresistance is crucial for improving clinical outcomes. In this study, AVIL was identified as a key gene correlated with OS progression and chemoresistance. AVIL overexpression was found to promote OS progression <em>in vitro</em> and <em>in vivo</em> by enhancing cell proliferation, migration, and invasion, while AVIL deficiency exerted the inverse phenotypes. <em>In vivo</em> experiments further confirmed that AVIL overexpression promotes tumor growth and suppresses apoptosis. Mechanistically, AVIL interacts with the ARP2/3 complex, a key regulator of DNA damage repair via actin polymerization and cytoskeletal dynamics. This interaction was confirmed to facilitate cisplatin resistance, with reduced DNA damage response and increased cell survival caused by AVIL overexpression. Furthermore, using patient-derived organoid (PDO) models, we demonstrated that CK666, an ARP2/3 inhibitor, enhanced the chemotherapy efficacy of cisplatin by increasing DNA damage response and reversing AVIL-mediated cisplatin resistance. These findings highlight AVIL as a potential therapeutic target and suggest that targeting the AVIL-ARP2/3 axis could serve as an alternative strategy to overcome chemoresistance during OS treatment.</div></div>","PeriodicalId":48975,"journal":{"name":"Translational Oncology","volume":"64 ","pages":"Article 102654"},"PeriodicalIF":5.0,"publicationDate":"2026-01-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145913261","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"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