Translational Oncology最新文献_第7页

Prediction of local recurrence in cohorts of head and neck cancer patients after intensity-modulated radiation therapy based on CT radiomics: A double-center observation study 基于CT放射组学的调强放疗后头颈癌患者局部复发预测：一项双中心观察研究

IF 5 2区医学 Q2 Medicine

Translational Oncology

Pub Date : 2025-12-03 DOI: 10.1016/j.tranon.2025.102622

Jing Xu, Qing Liu, Yue Yin, Junhang Gao, Guanglu Dong

Objective

This study aims to develop and validate a CT-based radiomics model for predicting the prognosis of head and neck cancer patients, particularly those with nasopharyngeal carcinoma (NPC), following intensity-modulated radiation therapy (IMRT).

Methods

We conducted a retrospective analysis involving 392 pathologically confirmed NPC patients from two centers. Center A contributed 226 patients to the training cohort, while Center B provided 64 patients for the validation cohort. Features extracted from CT images were utilized to develop two predictive models: a clinically combined radiomics model and a standalone radiomics model. Dimensionality reduction and nested cross-validation were employed in the model development process. The performance of the models was assessed and validated using receiver operating characteristic (ROC) curves and decision curve analysis (DCA), with differences between the models evaluated using the DeLong test.

Results

Our findings indicate that the clinically combined radiomics model outperforms the standalone radiomics model in prognostic prediction. The area under the curve (AUC) for the combined model was 0.90 in the training cohort, while the validation cohort achieved an AUC of 0.86. DCA further confirmed that the performance of all models exceeded that of blindly predicting patient outcomes as either all negative or all positive. Subsequent comparisons using the DeLong test revealed significant differences in predictive performance between the standalone radiomics model and the clinically combined radiomics model, with P-values <0.05.

Conclusion

The clinically combined radiomics model demonstrates promising performance in predicting the prognosis of NPC patients following IMRT.

目的：本研究旨在建立并验证一种基于ct的放射组学模型，用于预测头颈癌患者，特别是鼻咽癌（NPC）患者在调强放疗（IMRT）后的预后。方法：我们对来自两个中心的392例经病理证实的鼻咽癌患者进行回顾性分析。A中心为培训队列提供226例患者，B中心为验证队列提供64例患者。利用从CT图像中提取的特征建立两种预测模型：临床联合放射组学模型和独立放射组学模型。在模型开发过程中采用了降维和嵌套交叉验证。采用受试者工作特征（ROC）曲线和决策曲线分析（DCA）对模型的性能进行评估和验证，采用DeLong检验评估模型之间的差异。结果：我们的研究结果表明，临床联合放射组学模型在预后预测方面优于单独放射组学模型。在训练队列中，联合模型的曲线下面积（AUC）为0.90，而验证队列的AUC为0.86。DCA进一步证实，所有模型的表现都超过了盲目预测患者预后为全阴性或全阳性的表现。随后使用DeLong检验进行比较，发现独立放射组学模型与临床联合放射组学模型的预测性能存在显著差异，p值为p值。结论：临床联合放射组学模型在预测鼻咽癌患者IMRT后预后方面表现良好。

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引用次数: 0

Biomarker analysis from a Phase 1/1b study of tusamitamab ravtansine in patients with advanced non-small cell lung cancer tusamitamab ravtansine在晚期非小细胞肺癌患者中的1/1b期研究的生物标志物分析。

IF 5 2区医学 Q2 Medicine

Translational Oncology

Pub Date : 2025-12-03 DOI: 10.1016/j.tranon.2025.102615

Anas Gazzah , Nils Ternès , Joon Sang Lee , Emma Wang , Dimitri Carene , Hong Wang , Nina Masson , Eric Boitier , Aude Lartigau , Nathalie Mace , Mustapha Chadjaa , Colette Dib , Manoel Nunes , Gaëlle Muzard , Sandrine Longuemaux-Valence , Anne-Laure Bauchet

Background

Tusamitamab ravtansine demonstrated antitumor activity in the Phase 1/1b study of advanced non-squamous non-small cell lung cancer with high (HE, ≥2+ intensity in ≥50 % of tumor cells) or moderate (ME, ≥2+ intensity in ≥1 % to <50 % of tumor cells) carcinoembryonic antigen-related cell adhesion molecule 5 (CEACAM5) expression. Tumor CEACAM5 expression, biomarker associations and whether biomarkers predict objective response rate (ORR) were explored.

Methods

We assessed CEACAM5, circulating CEACAM5 (cCEACAM5) and CEA (cCEA). Enrollment was according to immunohistochemistry (IHC) CEACAM5 membrane expression: HE (n=64) and ME (n=28). Patients received tusamitamab ravtansine 100 mg/m² intravenously every 2 weeks.

Results

cCEA and cCEACAM5 were strongly associated (Spearman ρ, 0.99), with moderate associations between IHC CEACAM5 and cCEA or cCEACAM5 (Spearman ρ, 0.43 and 0.38). In patients with baseline cCEA data, 40.3 % (25/62) of HE and 25 % (7/28) of ME had cCEA ≥100 µg/L (median: 71.6 µg/L [1–8809] versus 12.4 µg/L [0.5–684]). Among response-evaluable patients in HE, ORR for high cCEA (≥100 µg/L) was 41.7 % (10/24) versus 8.1 % (3/37) for low cCEA, and in ME, ORR was 0/7 versus 10 % (2/20). Elevated CEACAM5 mRNA was observed in HE versus ME (P = 0.0027). EGFR and KRAS alterations were present in 44.8 % and 65.5 % of HE and in 21.4 % and 78.6 % of ME patients, respectively.

Conclusions

In CEACAM5 HE, the ORR was greater with high versus low cCEA. Associations were observed between cCEA and cCEACAM5; IHC CEACAM5, cCEA, and cCEACAM5; IHC CEACAM5 and CEACAM5 mRNA, but not between IHC CEACAM5 and oncogenic drivers.

Clinical Trial Registration: NCT02187848

背景：Tusamitamab ravtansine在晚期非鳞状非小细胞肺癌的1/1b期研究中显示出高（HE，≥50%肿瘤细胞≥2+强度）或中等（ME，≥1%肿瘤细胞≥2+强度）的抗肿瘤活性。方法：我们评估了CEACAM5、循环CEACAM5 （cCEACAM5）和CEA （cCEA）。根据免疫组化（IHC） CEACAM5膜表达入组：HE （n=64）和ME （n=28）。患者静脉注射tusamitamab ravtansine 100mg /m2，每2周一次。结果：cCEA与cCEACAM5呈正相关（Spearman ρ, 0.99）， IHC CEACAM5与cCEA或cCEACAM5呈正相关（Spearman ρ， 0.43和0.38）。在基线cCEA数据的患者中，40.3%（25/62）的HE和25%（7/28）的ME的cCEA≥100µg/L（中位数：71.6µg/L [1-8809] vs 12.4µg/L[0.5-684]）。在HE组反应可评估的患者中，高cCEA（≥100µg/L）的ORR为41.7%(10/24)，而低cCEA的ORR为8.1%(3/37)，在ME组，ORR为0/7，而10%（2/20）。HE组与ME组CEACAM5 mRNA升高（P = 0.0027）。EGFR和KRAS的改变在HE患者中分别为44.8%和65.5%，在ME患者中分别为21.4%和78.6%。结论：在CEACAM5 HE中，高cCEA比低cCEA的ORR更大。cCEA与cCEACAM5存在相关性；IHC CEACAM5、cCEA和cCEACAM5；IHC CEACAM5和CEACAM5 mRNA，但在IHC CEACAM5和致癌驱动因子之间不存在差异。临床试验注册：NCT02187848。

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引用次数: 0

Poly-ADP-ribosylation modulated by poly(ADP-ribose) polymerase 1 is associated with glucose metabolism in colorectal cancer cells poly（adp -核糖）聚合酶1调控的poly - adp核糖基化与结直肠癌细胞的糖代谢有关。

IF 5 2区医学 Q2 Medicine

Translational Oncology

Pub Date : 2025-12-03 DOI: 10.1016/j.tranon.2025.102623

Chenxuan Zhang , Peng Wang , Jia Yu , Jianhui Yuan , Lilong Zhang , Man Li

The preference of cancer cells to generate energy from glycolysis for rapid cell proliferation is called the Warburg effect. Poly(ADP-ribose) polymerase 1 (PARP1) performs various cellular functions, including poly-ADP-ribosylation and DNA repair. In the present study, we investigated the novel effects and mechanisms of PARP1 inhibition on glucose metabolism in colorectal cancer cells under hypoxia. We subjected Caco-2 and LoVo cancer cell lines to a concentration gradient of PARP1 inhibitor in a hypoxic environment induced with a tri-gas incubator (5 % CO₂, 1 % O₂, 94 % N₂). Inhibiting PARP1 activation attenuated Poly-ADP-ribosylation, increasing the NAD⁺/NADH ratio. High concentrations of PARP1 significantly reduced the glucose consumption rate of the treated cells, while PARP1 inhibition depressed cell progression in a concentration-dependent manner. The expression of hypoxia-inducible factor-1α (HIF-1α), hexokinase 2 (HK2), and glucose transporter 1 (GLUT-1), critical for the Warburg effect and glucose metabolism, was considerably reduced after the inhibitor treatments. Moreover, inhibiting PARP1 activation reduced phosphorylated AKT (p-AKT) and mTOR (p-mTOR) levels. In conclusion, our study revealed that PARP1 inhibition decelerates the Warburg effect in colorectal cancer cells, likely through the AKT/mTOR/HIF-1α pathway.

癌细胞倾向于通过糖酵解产生能量，以促进细胞快速增殖，这种现象被称为Warburg效应。聚（adp -核糖）聚合酶1 （PARP1）具有多种细胞功能，包括聚adp -核糖基化和DNA修复。在本研究中，我们研究了缺氧条件下PARP1抑制结直肠癌细胞糖代谢的新作用和机制。我们在三气培养箱（5% CO2, 1% O2, 94% N2）诱导的缺氧环境中，将Caco-2和LoVo癌细胞置于PARP1抑制剂的浓度梯度中。抑制PARP1激活可减弱poly - adp核糖基化，增加NAD+/NADH比值。高浓度的PARP1显著降低了处理细胞的葡萄糖消耗率，而PARP1抑制以浓度依赖的方式抑制细胞进展。低氧诱导因子-1α (HIF-1α)、己糖激酶2 （HK2）和葡萄糖转运蛋白1 （GLUT-1）的表达在抑制剂处理后显著降低，这对Warburg效应和葡萄糖代谢至关重要。此外，抑制PARP1激活可降低磷酸化AKT （p-AKT）和mTOR （p-mTOR）水平。总之，我们的研究表明，PARP1抑制可能通过AKT/mTOR/HIF-1α途径减缓结直肠癌细胞中的Warburg效应。

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引用次数: 0

The PI3K pathway is a downstream effector of NRF2 activation in the esophagus PI3K通路是NRF2在食道中激活的下游效应。

IF 5 2区医学 Q2 Medicine

Translational Oncology

Pub Date : 2025-12-03 DOI: 10.1016/j.tranon.2025.102629

Boopathi Subramaniyan , Yahui Li , Zhaohui Xiong , Chorlada Paiboonrungruang , Candice Bui-Linh , Francis Spitz , Xiaoxin Chen

Mutations in nuclear factor erythroid 2–related factor 2 (NFE2L2 or NRF2) occur in 10–22 % of esophageal squamous cell carcinoma (ESCC) cases and result in NRF2 activation, promoting tumor progression, and therapeutic resistance. Although previous studies suggested a link between NRF2 and kinases, specific kinases responsive to NRF2 activation remain to be fully identified. Using protein phosphorylation profiling and kinase activity profiling, we identified phosphatidylinositol 3-kinase (PI3K) pathway as a downstream effector in NRF2^W24C-KYSE70 cells compared to isogenic NRF2^null-KYSE70 cells. AREG, pEGFR, PIK3CA, pAKT, p-S6, and p-PTEN were downregulated in NRF2 deficient cells. Notably, NRF2 deficiency sensitized ESCC cells to EGFR, PIK3CA, and AKT inhibitors. Co-treatment with Alpelisib (a PIK3CA inhibitor) and Pyrimethamine (an NRF2 inhibitor) synergistically suppressed the growth of NRF2^W24C-KYSE70 and NRF2^D77V-KYSE180 cells. In vivo, NRF2 activation in the esophageal epithelium of Keap1^-/- and Sox2CreER;LSL-Nrf2^E79Q/+ mice resulted in upregulation of pAKT, p-mTOR, and pS6. In human ESCC tissues, expression of pNRF2 (an active form of NRF2) was positively associated with that of pAKT and p-mTOR. Furthermore, co-treatment with Pyrimethamine and Alpelisib significantly inhibited hyperproliferation and hyperkeratinization in the esophageal epithelium of Sox2CreER;LSL-Nrf2^E79Q/+mice. Together, our data demonstrates the PI3K pathway as a downstream effector of NRF2 activation in the esophagus, and co-targeting of NRF2 and the PI3K pathway may offer a promising therapeutic strategy for NRF2^Mut ESCC.

10- 22%的食管鳞状细胞癌（ESCC）病例发生核因子红系2相关因子2 （NFE2L2或NRF2）突变，导致NRF2激活，促进肿瘤进展和治疗耐药。尽管先前的研究表明NRF2与激酶之间存在联系，但对NRF2激活有反应的特定激酶仍有待完全确定。通过蛋白磷酸化分析和激酶活性分析，我们发现与等基因NRF2W24C-KYSE70细胞相比，NRF2W24C-KYSE70细胞中的PI3K通路是下游效应物。AREG、pEGFR、PIK3CA、pAKT、p-S6和p-PTEN在NRF2缺陷细胞中下调。值得注意的是，NRF2缺乏使ESCC细胞对EGFR、PIK3CA和AKT抑制剂敏感。Alpelisib（一种PIK3CA抑制剂）和Pyrimethamine（一种NRF2抑制剂）协同抑制NRF2W24C-KYSE70和NRF2D77V-KYSE180细胞的生长。在体内，NRF2在Keap1-/-和Sox2CreER的食管上皮中活化；LSL-Nrf2E79Q/+小鼠导致pAKT、p-mTOR和pS6的上调。在人ESCC组织中，pNRF2 （NRF2的一种活性形式）的表达与pAKT和p-mTOR的表达呈正相关。此外，乙胺嘧啶和Alpelisib联合治疗可显著抑制Sox2CreER；LSL-Nrf2E79Q/+小鼠食管上皮的过度增生和角化过度。综上所述，我们的数据表明PI3K通路是NRF2在食管中激活的下游效应物，同时靶向NRF2和PI3K通路可能为NRF2Mut ESCC提供一种有希望的治疗策略。

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引用次数: 0

piR-43452 suppresses bladder cancer progression and enhances gemcitabine sensitivity via GTSF1/PIWIL4-mediated LRP1 mRNA destabilization piR-43452通过GTSF1/ piwil4介导的LRP1 mRNA失稳抑制膀胱癌进展并增强吉西他滨敏感性。

IF 5 2区医学 Q2 Medicine

Translational Oncology

Pub Date : 2025-12-03 DOI: 10.1016/j.tranon.2025.102626

Yuchen Shi , Jiazhu Sun , Kai Yu , Dingheng Lu, Xinyang Niu, Yuxiao Li, Suyuelin Huang, Jindan Luo, Xiao Wang, Xueyou Ma, Jiangfeng Li, Yufan Ying, Liping Xie, Ben Liu

Piwi-interacting RNAs (piRNAs), while crucial for genomic integrity in germline cells, remain poorly characterized in somatic cancers. This study identifies piR-43452 as a significantly downregulated piRNA in bladder cancer (BCa), with loss of expression correlating clinically with muscle invasion and lymph node metastasis. Through assays in vitro and in vivo, we demonstrate that piR-43452 acts as a potent tumor suppressor, inhibiting BCa cell proliferation, migration, and xenograft growth while promoting apoptosis. Mechanistically, we identified that piR-43452 directly binds the 3′UTR of LRP1 mRNA and recruits the GTSF1/PIWIL4 complex, which enhances target cleavage through GTSF1-dependent conformational activation. This post-transcriptional regulation led to significant LRP1 suppression, subsequently inhibiting proliferation and restoring chemosensitivity. Our findings establish a novel piRNA-guided mechanism for overcoming chemoresistance and suggest that targeting the piR-43452/GTSF1/PIWIL4/LRP1 axis may provide therapeutic benefit in gemcitabine-resistant BCa.

piwi相互作用rna （pirna）虽然对生殖细胞的基因组完整性至关重要，但在体细胞癌症中仍然缺乏特征。本研究发现piR-43452在膀胱癌（BCa）中是一个显著下调的piRNA，其表达缺失在临床上与肌肉侵袭和淋巴结转移相关。通过体外和体内实验，我们证明了piR-43452作为一种有效的肿瘤抑制因子，抑制BCa细胞的增殖、迁移和异种移植物的生长，同时促进细胞凋亡。在机制上，我们发现piR-43452直接结合LRP1 mRNA的3'UTR并招募GTSF1/PIWIL4复合物，通过GTSF1依赖的构象激活增强目标切割。这种转录后调控导致显著的LRP1抑制，随后抑制增殖并恢复化学敏感性。我们的研究结果建立了一种新的pirna引导的克服化疗耐药的机制，并表明靶向piR-43452/GTSF1/PIWIL4/LRP1轴可能为吉西他滨耐药BCa提供治疗益处。

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引用次数: 0

A roadmap to unveil the mechanism(s) of natural indole-derived molecules against NAFLD-derived HCC via systems pharmacology 通过系统药理学揭示天然吲哚衍生分子对抗nafld衍生HCC机制的路线图。

IF 5 2区医学 Q2 Medicine

Translational Oncology

Pub Date : 2025-12-03 DOI: 10.1016/j.tranon.2025.102618

Ki-Kwang Oh , Goo-Hyun Kwon, Kyeong Jin Lee, Jung-A Eom , Dong Joon Kim, Ki-Tae Suk

Background

Non-alcoholic fatty liver disease (NAFLD) is involved in non-alcoholic steatohepatitis (NASH), liver cirrhosis (LC), and even hepatocellular carcinoma (HCC). Hence, this study was to elucidate nuanced key mechanism(s), target(s), and Natural Indole-Derived Molecules (NIDMs) against NAFLD-derived HCC.

Methods

The NIDMs were retrieved by Natural Product Activity & Species Source Database (NPASS). The protein-protein interaction (PPI) networks, bubble plot on key signaling pathways, etiological spectrum-signaling pathways-targets-indoles (ESTI) networks, the verification of toxicity on key NIDMs, and MDE (Molecular Docking Evaluation) were performed with integrating perspective.

Results

The 141 NIDMs were identified by NPASS and SwissADME, suggesting that the NIDMs were associated with Similarity Ensemble Approach (SEA; 845 targets) and SwissTargetPrediction (STP; 1107 targets). On PPI analysis, JUN was the uppermost target with the highest DV (Degree Value). A bubble plot based on rich factor constructed to identify key mechanism(s), suggesting that AGE-RAGE signaling pathway in diabetic complications might be key antagonistic mode to hinder the spontaneous progression of NAFLD. The key targets were JUN, and AGTR1 on AGE-RAGE signaling pathway in diabetic complications, binding most stably to Marinacarboline D, and Fumitremorgin F, respectively.

Conclusions

In closing, this study provides critical insights into the key mechanisms, targets, and NIDMs that may impede etiological spectrum of NAFLD.

背景：非酒精性脂肪性肝病（NAFLD）涉及非酒精性脂肪性肝炎（NASH）、肝硬化（LC），甚至肝细胞癌（HCC）。因此，本研究旨在阐明针对nafld来源的HCC的微妙关键机制、靶点和天然吲哚衍生分子（NIDMs）。方法：利用天然产物活性与物种来源数据库（NPASS）对nidm进行检索。以整合的视角进行蛋白-蛋白相互作用（PPI）网络、关键信号通路气泡图、病因谱-信号通路-靶标-吲哚（ESTI）网络、关键NIDMs毒性验证和MDE（分子对接评价）。结果：通过NPASS和SwissADME鉴定出141个nidm，表明nidm与相似集成方法（SEA； 845个靶点）和SwissTargetPrediction （STP； 1107个靶点）相关。在PPI分析中，JUN是最高的目标，DV（度值）最高。构建基于富因子的气泡图以确定关键机制，提示糖尿病并发症中的AGE-RAGE信号通路可能是阻碍NAFLD自发进展的关键拮抗模式。关键靶点是糖尿病并发症AGE-RAGE信号通路上的JUN和AGTR1，分别与marincarboline D和Fumitremorgin F结合最稳定。结论：总之，本研究为可能阻碍NAFLD病因谱的关键机制、靶点和nidm提供了重要的见解。

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引用次数: 0

The CHPT-pSTAT3-SLC7A11 signaling axis controls progression and ferroptosis susceptibility of pancreatic cancer CHPT-pSTAT3-SLC7A11信号轴控制胰腺癌的进展和铁下垂易感性。

IF 5 2区医学 Q2 Medicine

Translational Oncology

Pub Date : 2025-12-02 DOI: 10.1016/j.tranon.2025.102624

Jianhui Yang , Jiang Liu , Zeyin Rong , Zhen Tan , Wei Wang , Qingcai Meng , Miaoyan Wei , Jie Hua , Bo Zhang , Xianjun Yu , Jin Xu , Chen Liang

Background

Pancreatic ductal adenocarcinoma (PDAC) exhibits profound chemoresistance and metastasis, driving its dismal prognosis. Gemcitabine (GEM) resistance remains a critical barrier, necessitating exploration of metabolic regulators like choline phosphotransferase 1 (CHPT1) and ferroptosis in PDAC therapy.

Method

GEM-resistant PDAC cells were generated through stepwise induction. Metabolomics, RNA sequencing, and functional assays (CCK-8, EdU, Transwell) identified CHPT’s role. CHPT1 and SLC7A11 were genetically modulated using lentiviral vectors. Xenograft models assessed tumor growth.

Results

CHPT1 was downregulated in PDAC tissues and GEM-resistant cells. Restoring CHPT1 suppressed proliferation, migration, and epithelial–mesenchymal transition while enhancing GEM sensitivity. Mechanistically, CHPT1 recruited phosphatase PTPN1 to dephosphorylate STAT3 at Y705, inhibiting SLC7A11 transcription and triggering ferroptosis via lipid peroxidation. PTPN1 knockdown abolished CHPT1’s tumor-suppressive effects. Combining ferroptosis inducers (e.g., Erastin) with GEM synergistically inhibited tumor growth in vitro and in vivo.

Conclusion

The CHPT1-pSTAT3-SLC7A11 axis governs ferroptosis-dependent chemoresistance in PDAC. Dual targeting of CHPT1 and ferroptosis pathways represents a promising strategy to overcome GEM resistance, highlighting metabolic-kinase crosstalk as a therapeutic vulnerability.

背景：胰腺导管腺癌（Pancreatic ductal adenocarticoma， PDAC）表现出深刻的化疗耐药和转移，导致其预后不佳。吉西他滨（GEM）耐药性仍然是一个关键障碍，需要探索代谢调节因子，如胆碱磷酸转移酶1 （CHPT1）和PDAC治疗中的铁中毒。方法：采用逐级诱导法制备抗gem PDAC细胞。代谢组学、RNA测序和功能分析（CCK-8、EdU、Transwell）确定了CHPT的作用。利用慢病毒载体对CHPT1和SLC7A11进行基因调控。异种移植模型评估肿瘤生长情况。结果：CHPT1在PDAC组织和gem耐药细胞中表达下调。恢复CHPT1抑制增殖、迁移和上皮间质转化，同时增强GEM的敏感性。从机制上讲，CHPT1招募磷酸酶PTPN1使STAT3在Y705位点去磷酸化，抑制SLC7A11的转录，并通过脂质过氧化引发铁下垂。PTPN1敲除可消除CHPT1的肿瘤抑制作用。在体外和体内，将铁下垂诱导剂（如Erastin）与GEM联合使用可协同抑制肿瘤生长。结论：CHPT1-pSTAT3-SLC7A11轴调控PDAC铁凋亡依赖性化疗耐药。双重靶向CHPT1和ferroptosis途径代表了克服GEM耐药的有希望的策略，突出了代谢激酶串扰作为治疗脆弱性。

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引用次数: 0

From benchside avatars to bedside breakthroughs: Patient-derived organoids in the new era of cancer immunotherapy 从床边的化身到床边的突破：癌症免疫治疗新时代患者来源的类器官。

IF 5 2区医学 Q2 Medicine

Translational Oncology

Pub Date : 2025-12-01 DOI: 10.1016/j.tranon.2025.102619

Zhihui Mi , Hui Guan , Guodong Zhang , Dongyang Li , Yang Yu , Jialin Qu

The success of cancer immunotherapy is hampered by the lack of dynamic models that can predict patient-specific responses and guide the development of novel treatments. Static biomarkers, such as PD-L1 expression and tumor mutational burden, often fail to capture the complexity of the tumor-immune dialogue. Patient-derived tumor organoids (PDTOs) have emerged as a revolutionary ex vivo platform that bridges this gap. This review outlines the evolution of PDTOs from simple epithelial cultures to sophisticated, immune-competent "avatars" that faithfully recapitulate the patient's tumor microenvironment (TME). We critically discuss the key methodologies for reconstructing the TME, including "add-in" co-culture systems with diverse immune and stromal cells (e.g., T-cells, MDSCs, CAFs, neutrophils) and "all-in-one" approaches that preserve the native immune ecosystem. Furthermore, we highlight the expanding role of these advanced models beyond predicting checkpoint inhibitor efficacy. We showcase their groundbreaking applications as core development platforms for next-generation immunotherapies, including CAR-T cell therapy and the validation of personalized neoantigen-based vaccines. While acknowledging the significant translational challenges that remain, we conclude that immune-competent PDTOs represent an indispensable tool poised to accelerate the new era of precision immuno-oncology.

由于缺乏能够预测患者特异性反应和指导新疗法发展的动态模型，癌症免疫治疗的成功受到了阻碍。静态生物标志物，如PD-L1表达和肿瘤突变负担，往往无法捕捉肿瘤-免疫对话的复杂性。患者源性肿瘤类器官（PDTOs）作为一种革命性的离体平台出现，弥补了这一差距。这篇综述概述了pdto从简单的上皮培养到复杂的、具有免疫能力的“化身”的演变，这些“化身”忠实地概括了患者的肿瘤微环境（TME）。我们批判性地讨论了重建TME的关键方法，包括“附加”与多种免疫细胞和基质细胞（如t细胞、MDSCs、CAFs、中性粒细胞）的共培养系统，以及保护天然免疫生态系统的“一体化”方法。此外，我们强调了这些先进模型在预测检查点抑制剂疗效之外的扩展作用。我们展示了它们的突破性应用，作为下一代免疫疗法的核心开发平台，包括CAR-T细胞疗法和个性化新抗原疫苗的验证。虽然承认仍然存在重大的转化挑战，但我们得出结论，免疫活性pdto代表了加速精确免疫肿瘤学新时代的不可或缺的工具。

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引用次数: 0

Circular RNA circAHSA1 serves as a stable serum biomarker for the diagnosis and progression of gastric cancer 环状RNA circAHSA1作为胃癌诊断和进展的稳定血清生物标志物。

IF 5 2区医学 Q2 Medicine

Translational Oncology

Pub Date : 2025-12-01 DOI: 10.1016/j.tranon.2025.102620

Jiayi He , Shuo Ma , Shougang Kuai , Shaoqing Ju

Background

Gastric cancer (GC) remains a major cause of cancer-related mortality globally, largely due to the absence of reliable non-invasive biomarkers for early detection. Circular RNAs (circRNAs), characterized by covalently closed-loop structures, stability, and detectability in circulation, have emerged as promising liquid biopsy candidates.

Methods

circAHSA1 (hsa_circ_0032777) was identified through GEO dataset screening (GSE121445) and validated in GC tissues, serum, and cell lines using qRT-PCR with optimized internal reference selection. Diagnostic performance was assessed using ROC analysis and DeLong tests, evaluating circAHSA1 alone and in combination with CEA, CA199, and CA724. Biological functions were examined through proliferation, apoptosis, migration, and invasion assays. Subcellular localization and potential downstream miRNA interactions were analyzed using nuclear–cytoplasmic fractionation and multi-database bioinformatic prediction.

Results

circAHSA1 expression was significantly elevated in GC tissues, serum, and cell lines, and correlated with lymph node metastasis, differentiation status, and TNM stage. Serum circAHSA1 effectively discriminated GC from healthy controls (AUC = 0.787) and gastritis patients (AUC = 0.752), outperforming conventional markers, with statistical superiority confirmed by DeLong analysis. Combined detection further improved diagnostic accuracy (AUC = 0.871). Functionally, silencing circAHSA1 suppressed GC cell proliferation, migration, and invasion while enhancing apoptosis and inducing cell-cycle arrest. Bioinformatic analysis suggested miR-647 and miR-661 as potential downstream targets.

Conclusions

circAHSA1 is a stable, GC-specific circulating biomarker with both diagnostic and functional relevance. These findings support circAHSA1 as a promising candidate for liquid biopsy-based GC detection and a potential therapeutic target.

背景：胃癌（GC）仍然是全球癌症相关死亡的主要原因，主要是由于缺乏可靠的非侵入性生物标志物用于早期检测。环状rna （circRNAs）具有共价闭环结构、稳定性和循环可检测性的特点，已成为有希望的液体活检候选者。方法：通过GEO数据集筛选（GSE121445）鉴定circAHSA1 (hsa_circ_0032777)，并使用优化的内参选择的qRT-PCR在GC组织、血清和细胞系中进行验证。采用ROC分析和DeLong检验评估诊断效能，单独评估circAHSA1，并与CEA、CA199和CA724联合评估。通过增殖、凋亡、迁移和侵袭试验检测生物功能。利用核细胞质分离和多数据库生物信息学预测分析了亚细胞定位和潜在的下游miRNA相互作用。结果：circAHSA1在胃癌组织、血清和细胞系中表达显著升高，与淋巴结转移、分化状态、TNM分期相关。血清circAHSA1能有效区分GC与健康对照（AUC = 0.787）和胃炎患者（AUC = 0.752），优于常规标志物，DeLong分析证实具有统计学优势。联合检测进一步提高了诊断准确率（AUC = 0.871）。功能上，沉默circAHSA1可抑制GC细胞的增殖、迁移和侵袭，同时增强细胞凋亡并诱导细胞周期阻滞。生物信息学分析提示miR-647和miR-661是潜在的下游靶点。结论：circAHSA1是一种稳定的gc特异性循环生物标志物，具有诊断和功能相关性。这些发现支持circAHSA1作为基于液体活检的GC检测的有希望的候选者和潜在的治疗靶点。

{"title":"Circular RNA circAHSA1 serves as a stable serum biomarker for the diagnosis and progression of gastric cancer","authors":"Jiayi He , Shuo Ma , Shougang Kuai , Shaoqing Ju","doi":"10.1016/j.tranon.2025.102620","DOIUrl":"10.1016/j.tranon.2025.102620","url":null,"abstract":"<div><h3>Background</h3><div>Gastric cancer (GC) remains a major cause of cancer-related mortality globally, largely due to the absence of reliable non-invasive biomarkers for early detection. Circular RNAs (circRNAs), characterized by covalently closed-loop structures, stability, and detectability in circulation, have emerged as promising liquid biopsy candidates.</div></div><div><h3>Methods</h3><div>circAHSA1 (hsa_circ_0032777) was identified through GEO dataset screening (GSE121445) and validated in GC tissues, serum, and cell lines using qRT-PCR with optimized internal reference selection. Diagnostic performance was assessed using ROC analysis and DeLong tests, evaluating circAHSA1 alone and in combination with CEA, CA199, and CA724. Biological functions were examined through proliferation, apoptosis, migration, and invasion assays. Subcellular localization and potential downstream miRNA interactions were analyzed using nuclear–cytoplasmic fractionation and multi-database bioinformatic prediction.</div></div><div><h3>Results</h3><div>circAHSA1 expression was significantly elevated in GC tissues, serum, and cell lines, and correlated with lymph node metastasis, differentiation status, and TNM stage. Serum circAHSA1 effectively discriminated GC from healthy controls (AUC = 0.787) and gastritis patients (AUC = 0.752), outperforming conventional markers, with statistical superiority confirmed by DeLong analysis. Combined detection further improved diagnostic accuracy (AUC = 0.871). Functionally, silencing circAHSA1 suppressed GC cell proliferation, migration, and invasion while enhancing apoptosis and inducing cell-cycle arrest. Bioinformatic analysis suggested miR-647 and miR-661 as potential downstream targets.</div></div><div><h3>Conclusions</h3><div>circAHSA1 is a stable, GC-specific circulating biomarker with both diagnostic and functional relevance. These findings support circAHSA1 as a promising candidate for liquid biopsy-based GC detection and a potential therapeutic target.</div></div>","PeriodicalId":48975,"journal":{"name":"Translational Oncology","volume":"63 ","pages":"Article 102620"},"PeriodicalIF":5.0,"publicationDate":"2025-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145661664","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

The prognostic value of tumor macroscopic morphology in colorectal cancer 肿瘤宏观形态对结直肠癌的预后价值

IF 5 2区医学 Q2 Medicine

Translational Oncology

Pub Date : 2025-11-29 DOI: 10.1016/j.tranon.2025.102607

Hsinyi Lin , Zimin Zhao , Yao Ma , Xiangchao Shi , Limei Guo , Junwei Wang , Wei Fu , Xin Zhou

Background

This study aims to evaluate the prognostic value of tumor macroscopic morphology in colorectal cancer (CRC) and understand the molecular mechanism behind different tumor morphologies.

Methods

642 eligible patients were enrolled in this study, including 335 patients in the prospective study and 307 patients in the retrospective study. CRCs were categorized into protruded, ulcerative, and infiltrative types according to our morphological classification, and their clinicopathological features and prognosis were analyzed. Furthermore, bulk RNA sequencing, single-cell RNA sequencing (scRNA-seq) and immunohistochemistry were performed to map the tumor microenvironment of different tumor morphologies.

Results

In the prospective cohort, CRC with infiltrative type were significantly associated with unfavorable clinicopathological characteristics and poor survival compared with ulcerative type and protruded type. Bulk RNA sequencing revealed that the infiltrative type correlated with higher expression of fibroblast activation protein-α (FAP), periostin and platelet endothelial cell adhesion molecule-1 (PECAM-1), which corresponded with elevated cell proportions of stromal cells and endothelial cells in scRNA-seq. Additionally, a retrospective cohort was conducted to assess the value of preoperative endoscopic morphology and radiological morphology, both independently associated with disease-free survival (DFS).

Conclusion

We proposed a revised tumor macroscopic morphology classification system in CRC. The infiltrative type is associated with poorer clinical outcomes, characterized by increased cancer-associated fibroblast (CAF) infiltration and enhanced angiogenesis compared with other types. Importantly, when expanded to endoscopy and CT preoperatively, both endoscopic and radiological morphology can serve as preoperative predictors of DFS.

本研究旨在评价肿瘤宏观形态在结直肠癌（CRC）中的预后价值，了解不同肿瘤形态背后的分子机制。方法642例患者入组，其中前瞻性研究335例，回顾性研究307例。根据形态学分类将crc分为突出型、溃疡型和浸润型，并对其临床病理特征和预后进行分析。此外，我们还进行了大量RNA测序、单细胞RNA测序（scRNA-seq）和免疫组织化学来绘制不同肿瘤形态的肿瘤微环境。结果在前瞻性队列中，浸润型结直肠癌与溃疡型和突出型结直肠癌相比，其临床病理特征和生存率均较差。大量RNA测序结果显示，浸润型与成纤维细胞活化蛋白-α (FAP)、骨膜蛋白和血小板内皮细胞粘附分子-1 （PECAM-1）的高表达相关，这与scRNA-seq中基质细胞和内皮细胞的细胞比例升高相对应。此外，进行了回顾性队列研究，以评估术前内镜形态学和放射学形态学的价值，两者都与无病生存（DFS）独立相关。结论我们提出了一种改进的CRC肿瘤宏观形态分类系统。浸润型与较差的临床结果相关，其特征是与其他类型相比，癌相关成纤维细胞（CAF）浸润增加，血管生成增强。重要的是，当术前扩展到内镜和CT时，内镜和放射学形态学都可以作为术前DFS的预测指标。

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引用次数: 0