Translational Oncology最新文献_第10页

Novel NOTCH2-NTRK1 fusion confers osimertinib resistance in EGFR-mutant non-small cell lung cancer by interacting with EGFR 新型NOTCH2-NTRK1融合通过与EGFR相互作用，在EGFR突变的非小细胞肺癌中赋予奥西替尼耐药性。

IF 5 2区医学 Q2 Medicine

Translational Oncology

Pub Date : 2025-11-25 DOI: 10.1016/j.tranon.2025.102577

Hui Li , Huiting Wei , Tiantian Zhen , Huabin Gao , Huicong Liu , Shuai Zheng , Huijuan Shi , Jiangtao Liang , Fenfen Zhang , Jiecheng Ye , Gengpeng Lin , Anjia Han

Background

Overcoming osimertinib resistance in epidermal growth factor receptor (EGFR) mutant non-small cell lung cancer (NSCLC) is challenging due to unclear mechanisms. We previously reported a NSCLC case with EGFR mutations progressed on osimertinib therapy, revealing a novel NOTCH2-NTRK1 fusion gene in the plasma and tumor tissue. Although the NTRK gene fusion has been identified in NSCLC and a range of tumor types, the role of NOTCH2-NTRK1 in osimertinib resistance is unclear.

Methods

We utilized both in vitro and in vivo models exhibiting NOTCH2-NTRK1 fusion positivity to explore the biological function of NOTCH2-NTRK1, as well as its role and mechanism in osimertinib resistance.

Results

The NOTCH2-NTRK1 fusion protein has been demonstrated to transform the human bronchial epithelial cell line BEAS-2B and promote the proliferation of NSCLC cells both in vitro and in vivo. It induces osimertinib resistance by activating MAPK and PI3K-AKT pathways. Phosphoproteomic analyses revealed a significant increase in the phosphorylation level of EGFR compared to the control group. Further investigations demonstrated that the NOTCH2-NTRK1 protein is capable of interacting with the EGFR protein. Protein molecular docking studies identified seven interacting sites between NOTCH2-NTRK1 and EGFR protein. Mutations within the region encompassing these seven interaction sites effectively reversed osimertinib resistance, leading to a significant reduction in the expression of key proteins within the MAPK and PI3K-AKT pathways. Notably, the interaction between NOTCH2-NTRK1 and EGFR was maintained even with combined osimertinib and entrectinib treatment.

Conclusion

Our study reveals a novel mechanism by which the NOTCH2-NTRK1 fusion confers resistance to osimertinib through its interaction with EGFR in NSCLC.

背景：克服表皮生长因子受体（EGFR）突变型非小细胞肺癌（NSCLC）的奥西替尼耐药是具有挑战性的，因为机制尚不清楚。我们之前报道了一例EGFR突变在奥西替尼治疗下进展的NSCLC病例，在血浆和肿瘤组织中发现了一种新的NOTCH2-NTRK1融合基因。尽管NTRK基因融合已在NSCLC和一系列肿瘤类型中被发现，但NOTCH2-NTRK1在奥希替尼耐药中的作用尚不清楚。方法：采用NOTCH2-NTRK1融合阳性的体内和体外模型，探讨NOTCH2-NTRK1的生物学功能及其在奥希替尼耐药中的作用和机制。结果：NOTCH2-NTRK1融合蛋白在体外和体内均可转化人支气管上皮细胞系BEAS-2B，促进NSCLC细胞的增殖。它通过激活MAPK和PI3K-AKT通路诱导奥希替尼耐药。磷酸化蛋白质组学分析显示，与对照组相比，EGFR的磷酸化水平显著增加。进一步的研究表明NOTCH2-NTRK1蛋白能够与EGFR蛋白相互作用。蛋白分子对接研究确定了NOTCH2-NTRK1与EGFR蛋白之间的7个相互作用位点。包含这七个相互作用位点的区域内的突变有效地逆转了奥西替尼耐药性，导致MAPK和PI3K-AKT通路中关键蛋白的表达显著降低。值得注意的是，即使在奥西替尼和恩替尼联合治疗的情况下，NOTCH2-NTRK1与EGFR之间的相互作用仍保持不变。结论：我们的研究揭示了NOTCH2-NTRK1融合通过与EGFR相互作用在非小细胞肺癌中赋予奥西替尼抗性的新机制。

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引用次数: 0

Clinical and molecular variations in Burkitt lymphoma 伯基特淋巴瘤的临床和分子变异

IF 5 2区医学 Q2 Medicine

Translational Oncology

Pub Date : 2025-11-25 DOI: 10.1016/j.tranon.2025.102611

Eoghan O’Connor , Patricia Scanlan , Owen Patrick Smith , Melinda Halasz

Burkitt lymphoma (BL) is an aggressive B-cell non-Hodgkin lymphoma, historically classified into three subtypes; endemic, sporadic and immunodeficiency associated BL. Accumulating evidence suggests that Epstein-Barr virus (EBV)-positive and EBV-negative BL represent biologically distinct entities. In this review, we aim to compare the clinicopathological and molecular differences in BL in the context of EBV status and chronic malaria infection.

From our review, clinical features of BL vary by both EBV status and geographical region, reflecting underlying epidemiological differences. The cell of origin may also differ between EBV-positive and EBV-negative cases. At a molecular level, differences based on EBV status include variations in the immunoglobulin (IG)::MYC translocation breakpoints, mutations in the inhibitor of DNA binding 3 (ID3)/ transcription factor 3 (TCF3)/ cyclin D3 (CCND3) signalling axis, the anti-apoptotic effects of EBV latency gene products, differences in the alternative reading frame (ARF)/ mouse double minute 2 (MDM2)/p53 and ataxia-telangiectasia mutated (ATM)/ ATM and RAD3-related (ATR) pathways, and deregulation of B-cell leukemia/lymphoma 2 (BCL-2) family proteins. We further discuss the theory that aberrant activation-induced cytidine deaminase (AID) expression, in the setting of EBV infection and chronic malaria exposure, is the most likely aetiology of endemic BL.

This review provides a comprehensive summary of key molecular differences between EBV-positive and EBV-negative BL, that may guide the development of future targeted therapeutic strategies.

伯基特淋巴瘤（BL）是一种侵袭性b细胞非霍奇金淋巴瘤，历史上分为三个亚型；越来越多的证据表明EBV阳性和EBV阴性的BL在生物学上是不同的实体。在这篇综述中，我们旨在比较EBV状态和慢性疟疾感染背景下BL的临床病理和分子差异。从我们的综述来看，EBV状态和地理区域不同，BL的临床特征也不同，反映了潜在的流行病学差异。在ebv阳性和ebv阴性病例中，起源细胞也可能不同。在分子水平上，基于EBV状态的差异包括免疫球蛋白（IG）： MYC易位断点的变化，DNA结合3 (ID3)/转录因子3 (TCF3)/细胞周期蛋白D3 （CCND3）信号轴的突变，EBV潜伏期基因产物的抗凋亡作用，替代阅读框(ARF)/小鼠双分钟2 (MDM2)/p53和失调性毛细血管扩张突变(ATM)/ ATM和rad3相关（ATR）途径的差异，b细胞白血病/淋巴瘤2 （BCL-2）家族蛋白的失调。我们进一步讨论了在EBV感染和慢性疟疾暴露的情况下，激活诱导的胞苷脱氨酶（AID）表达异常是最可能的地方流行BL病因的理论。本文综述了EBV阳性和EBV阴性BL之间的关键分子差异，这可能指导未来靶向治疗策略的发展。

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引用次数: 0

Apolipoprotein C1 functions as a target of thyroid carcinoma and synergistic effects with promising candidate-cyclopamine 载脂蛋白C1作为甲状腺癌的靶点及其与环巴胺的协同作用。

IF 5 2区医学 Q2 Medicine

Translational Oncology

Pub Date : 2025-11-24 DOI: 10.1016/j.tranon.2025.102617

Rui Wang , Bin Wang , Juanhong Shi , Zhi Zhu , ZhenZhen Yao

There is an urgent need to identify novel therapeutic targets for papillary thyroid carcinoma (PTC). APOC1 (Apolipoprotein C1) has emerged as a candidate: it is overexpressed in several cancers and its high expression often associates with worse clinical outcomes. Using bioinformatic analysis of TCGA-THCA RNA-seq data, we found that APOC1 is highly expressed in PTC and that elevated APOC1 correlates with poorer patient prognosis and with signatures of immune-evasion. We validated these observations in PTC cell lines. Immunofluorescence, colony-formation assays, CCK-8 proliferation measurements, and flow-cytometry apoptosis analysis all indicate that APOC1 promotes proliferation, enhances colony survival, and confers resistance to apoptosis. To identify candidate therapeutics that target APOC1-related pathways, we queried the Connectivity Map using shared differentially expressed genes (DEGs) and nominated cyclopamine as the top small-molecule hit. Cyclopamine reduces PTC cell proliferation and induces apoptosis in vitro; APOC1 depletion further sensitizes cells to cyclopamine, producing greater inhibition of proliferation and increased cell death. Finally, cyclopamine suppresses tumor growth in a PTC mouse model. Together, these results implicate APOC1 as a driver of PTC progression and immune evasion and identify cyclopamine as a promising therapeutic that acts, at least in part, through APOC1-related signaling. Our study thus provides a rationale for targeting APOC1 as a novel treatment strategy for papillary thyroid carcinoma.

目前迫切需要寻找新的治疗甲状腺乳头状癌（PTC）的靶点。apop1（载脂蛋白C1）已成为候选：它在几种癌症中过表达，其高表达通常与较差的临床结果相关。通过TCGA-THCA RNA-seq数据的生物信息学分析，我们发现APOC1在PTC中高表达，并且增高的APOC1与较差的患者预后和免疫逃避特征相关。我们在PTC细胞系中验证了这些观察结果。免疫荧光、集落形成实验、CCK-8增殖测量和流式细胞术细胞凋亡分析均表明，APOC1促进增殖，提高集落存活，并赋予细胞凋亡抗性。为了确定靶向apoc1相关通路的候选疗法，我们使用共享差异表达基因（DEGs）查询了连接图，并提名环巴胺作为首选小分子靶点。环巴胺抑制PTC细胞增殖，诱导细胞凋亡；APOC1缺失进一步使细胞对环巴胺敏感，产生更大的增殖抑制和增加细胞死亡。最后，环巴胺抑制PTC小鼠模型中的肿瘤生长。总之，这些结果表明APOC1是PTC进展和免疫逃避的驱动因素，并确定环巴胺是一种有希望的治疗方法，至少部分通过APOC1相关信号传导起作用。因此，我们的研究为靶向APOC1作为治疗甲状腺乳头状癌的新策略提供了理论依据。

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引用次数: 0

Bmi-1 inhibition sensitizes head and neck cancer stem cells to cytotoxic chemotherapy Bmi-1抑制使头颈癌干细胞对细胞毒性化疗敏感。

IF 5 2区医学 Q2 Medicine

Translational Oncology

Pub Date : 2025-11-24 DOI: 10.1016/j.tranon.2025.102603

Alexandra E. Herzog , Shirley Zheng , Kristy A. Warner , Jaqueline V. Vanini , Ritu Somayaji , Madelynn R. Johnson , Zhaocheng Zhang , Peter J. Polverini , Rogério M Castilho , Alexander T. Pearson , Jacques E. Nör

Cancer stem cells (CSC) drive therapeutic resistance and recurrence in head and neck squamous cell carcinoma (HNSCC). We and others have shown that treatment with cytotoxic chemotherapy agents (e.g. Cisplatin, Carboplatin) induce Bmi-1 expression and increase the fraction of highly tumorigenic CSC in HNSCC. Notably, Bmi-1 is a master regulator of stem cell self-renewal and DNA repair. The purpose of this work was to test whether therapeutic inhibition of Bmi-1 sensitizes HNSCC cancer stem cells to chemotherapy. HNSCC cells (UM-SCC-1,-22A,-22B) were treated with Cisplatin or Carboplatin and subjected to stemness analyses to evaluate the impact of Bmi-1 on chemoresistance. We observed that both, shRNA-mediated Bmi-1 silencing or pharmacologic inhibition of Bmi-1 with the small molecule inhibitor PTC596, blocked chemotherapy-induced cancer stemness (i.e. increase in the fraction of ALDH^highCD44^high cells), CSC self-renewal (i.e. orosphere formation) and inhibited protective DNA damage responses in HNSCC. Further, it is known that high IL-6 serum levels correlate with poor HNSCC patient survival, and that platinum-based therapies induce IL-6 signaling. Here, we observed that Bmi-1 silencing (or PTC596 treatment) inhibited the IL-6R/STAT3 signaling pathway even in presence of platinum-based cytotoxic agents (i.e. Cisplatin, Carboplatin). In vivo, Bmi-1 inhibition with PTC596 suppressed Cisplatin-mediated increase in the fraction of ALDH^highCD44^high cells (cancer stemness). Collectively, these preclinical results demonstrate that Bmi-1 is a key mediator of head and neck cancer stemness and suggest that HNSCC patients might benefit from treatment with a Bmi-1 inhibitor combined with a conventional chemotherapeutic agent.

肿瘤干细胞（CSC）驱动头颈部鳞状细胞癌（HNSCC）的治疗抵抗和复发。我们和其他人已经表明，使用细胞毒性化疗药物（如顺铂、卡铂）治疗可诱导Bmi-1表达，并增加HNSCC中高度致瘤性CSC的比例。值得注意的是，Bmi-1是干细胞自我更新和DNA修复的主要调节因子。这项工作的目的是测试治疗性抑制Bmi-1是否会使HNSCC癌症干细胞对化疗敏感。用顺铂或卡铂处理HNSCC细胞（UM-SCC-1,-22A,-22B），并进行干细胞分析以评估Bmi-1对化疗耐药的影响。我们观察到shrna介导的Bmi-1沉默或用小分子抑制剂PTC596对Bmi-1进行药理学抑制，都可以阻断化疗诱导的癌症干细胞（即aldhhighcd44 - high细胞的比例增加）、CSC自我更新（即orosphere形成）并抑制HNSCC中的保护性DNA损伤反应。此外，已知高血清IL-6水平与HNSCC患者生存率低相关，并且基于铂的治疗诱导IL-6信号传导。在这里，我们观察到Bmi-1沉默（或PTC596治疗）即使存在铂基细胞毒性药物（即顺铂，卡铂）也能抑制IL-6R/STAT3信号通路。在体内，PTC596抑制Bmi-1抑制顺铂介导的aldhhighcd44高细胞比例的增加（癌性）。总的来说，这些临床前结果表明，Bmi-1是头颈癌发病的关键介质，并表明HNSCC患者可能受益于Bmi-1抑制剂联合常规化疗药物的治疗。

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引用次数: 0

β-Sitosterol enhances the anti-tumor efficacy of sorafenib in hepatocellular carcinoma via the FXR/LXR/ SREBP1/ FASN pathway β-谷甾醇通过FXR/LXR/ SREBP1/ FASN通路增强索拉非尼在肝癌中的抗肿瘤作用。

IF 5 2区医学 Q2 Medicine

Translational Oncology

Pub Date : 2025-11-23 DOI: 10.1016/j.tranon.2025.102610

Aiwen Yan , Zihan Huang , Liang Kong , Zhaoyan Cheng , Yuewen Song , Xiaomao Li , Pan Jiang , Yuhui Yan

Objective: To investigate whether β-Sitosterol (SIT) enhanced the anticarcinogenic effects of sorafenib on HCC. Methods: The anti-tumor effects in vitro were detected using a Cell Counting Kit-8 assay, 5-ethynyl-29-deoxyuridine assay, flow cytometry, wound healing assay and tube formation assay. Blood samples were collected for in vivo biochemical and metabolomic analyses. Anticarcinogenic activity was evaluated by Masson’s trichrome staining in conjunction with hematoxylin and eosin staining. Bioinformatics analyses were conducted to investigate the potential associations between lipid metabolism and HCC. Finally, the lipid- related protein expression was detected by immunohistochemical staining (IHC) and western blot (WB) analysis. Results: In vitro studies demonstrated that the combination of SIT and sorafenib promoted apoptosis and inhibited the growth, proliferation, migration and vasculogenic mimicry formation and of HCC cells. Additionally, the anti-hepatocarcinoma activity of the combination treatment was better than that of sorafenib treatment alone to inhibit diethylnitrosamine-induced HCC progression. Metabolomic, bioinformatics, IHC and WB analyses suggest that SIT regulates lipid metabolism by modulating the expression of FXR, LXR, SREBP1, and FASN. Conclusions: The data suggest that SIT enhances the effect of sorafenib by regulating lipid metabolism targeting FXR, LXR, SREBP1, and FASN, indicating that the strategies to union potent drugs regulating lipid metabolism with sorafenib deserves to be further explored.

目的：探讨β-谷甾醇（SIT）是否能增强索拉非尼对肝癌的抗癌作用。方法：采用细胞计数试剂盒-8法、5-乙基-29-脱氧尿苷法、流式细胞术、伤口愈合法和成管法检测其体外抗肿瘤作用。采集血液样本进行体内生化和代谢组学分析。马松三色染色联合苏木精和伊红染色评价其抗癌活性。进行生物信息学分析以研究脂质代谢与HCC之间的潜在关联。最后通过免疫组化染色（IHC）和免疫印迹（WB）检测脂质相关蛋白的表达。结果：体外研究表明，SIT联合索拉非尼可促进细胞凋亡，抑制肝癌细胞的生长、增殖、迁移和血管模拟形成。此外，联合治疗在抑制二乙基亚硝胺诱导的HCC进展方面的抗肝癌活性优于单用索拉非尼治疗。代谢组学、生物信息学、IHC和WB分析表明，SIT通过调节FXR、LXR、SREBP1和FASN的表达来调节脂质代谢。结论：数据提示，SIT通过靶向FXR、LXR、SREBP1和FASN调节脂质代谢来增强索拉非尼的作用，提示强效调节脂质代谢药物与索拉非尼联合的策略值得进一步探索。

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引用次数: 0

L-theanine's therapeutic effects on colorectal cancer: Mechanistic insights from a 1,2-dimethylhydrazine-induced rat model l -茶氨酸对结直肠癌的治疗作用：1,2-二甲基肼诱导大鼠模型的机制见解

IF 5 2区医学 Q2 Medicine

Translational Oncology

Pub Date : 2025-11-22 DOI: 10.1016/j.tranon.2025.102609

Jimusi , Yanfeng Han , Xiaohua Su , Qi Li , Siying Liu , Siying Cheng , Weiquan Shen , Junchu He , Yuesitu , Nashunbayaer

This study aimed to elucidate the novel effects and underlying mechanisms of L-theanine on colorectal cancer (CRC) in a rat model. Specifically, it focused on how L-theanine uniquely impacts cell proliferation, apoptosis, epithelial-mesenchymal transition (EMT), oxidative stress, inflammation, intestinal microbiota, and short-chain fatty acids in rat CRC compared to existing studies. In the 1,2-dimethylhydrazine (DMH) group, serum levels of CRP, AFP, CEA, and CA199 were elevated compared to controls, but L-theanine treatment reduced these levels. IHC analysis showed a significant decrease in Ki67-positive cells in colon tissues with L-theanine. HE staining indicated improved colon pathology, and TUNEL assays revealed increased apoptosis. Western blotting demonstrated up-regulation of caspase-3, cleaved caspase-3, and Bax, and down-regulation of Bcl-2 with L-theanine. It also corrected abnormal expressions of tumor and EMT markers. L-theanine reduced oxidative stress and inflammation by boosting CAT activity, SOD, and GSH levels, while decreasing MDA content and ROS intensity in CRC rats. It decreased pro-inflammatory cytokines IL-1β, TNF-α, and IL-6, increased anti-inflammatory IL-10, and reduced COX2, NF-κB p65, and NLRP3 protein levels. L-theanine altered the gut microbiota composition in CRC rat models, resulting in 379 new strains and reduced levels of genera like Kineothrix and Parasutterella. Immunohistochemical analysis showed increased GPR41 expression in the DMH group versus controls. These novel findings suggest L-theanine’s potential as a distinct chemopreventive agent for CRC due to its beneficial and unique effects.

本研究旨在阐明l -茶氨酸对大鼠结直肠癌（CRC）的新作用及其机制。具体而言，与现有研究相比，该研究侧重于l-茶氨酸如何独特地影响大鼠结直肠癌中的细胞增殖、凋亡、上皮-间质转化（EMT）、氧化应激、炎症、肠道微生物群和短链脂肪酸。在1,2-二甲基肼（DMH）组中，与对照组相比，血清CRP、AFP、CEA和CA199水平升高，但l -茶氨酸治疗降低了这些水平。免疫组化分析显示，加入l -茶氨酸后，结肠组织中ki67阳性细胞显著减少。HE染色显示结肠病理改善，TUNEL检测显示细胞凋亡增加。Western blot结果显示，l-茶氨酸上调caspase-3、cleaved - caspase-3和Bax，下调Bcl-2。它还纠正了肿瘤和EMT标志物的异常表达。l -茶氨酸通过提高CRC大鼠CAT活性、SOD和GSH水平，同时降低MDA含量和ROS强度，从而降低氧化应激和炎症。降低促炎因子IL-1β、TNF-α、IL-6，升高抗炎因子IL-10，降低COX2、NF-κB p65、NLRP3蛋白水平。l -茶氨酸改变了CRC大鼠模型中的肠道微生物群组成，导致379个新菌株和Kineothrix和Parasutterella等属的水平降低。免疫组织化学分析显示，与对照组相比，DMH组GPR41表达增加。这些新发现表明，由于l -茶氨酸有益和独特的作用，它有可能成为一种独特的结直肠癌化学预防剂。

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引用次数: 0

Multi-omics analysis reveals the heterogeneity and interactions among stromal and tumor cells in gastric cancer 多组学分析揭示了胃癌间质细胞和肿瘤细胞之间的异质性和相互作用。

IF 5 2区医学 Q2 Medicine

Translational Oncology

Pub Date : 2025-11-22 DOI: 10.1016/j.tranon.2025.102614

Chenyu Yang , Yue Jin , Xiaoyi Zhao , Lingyi Zhou , Xinrong Xu , Qiang Zhan , Qinglin Zhang

Objective

This study aims to investigate the heterogeneity of cancer-associated fibroblasts (CAFs) and smooth muscle cells (SMCs) and their interactions with malignant epithelium in gastric cancer (GC), with the goal of identifying potential therapeutic targets.

Methods

We performed a multi-omics analysis integrating single-cell RNA sequencing and spatial transcriptomics, complemented by trajectory inference, regulon activity mapping, ligand-receptor interaction modeling, and survival association in external cohorts.

Results

Two malignant epithelial programs emerged—Tumor Cell 1 (TC 1) (wound-healing/proliferative) and Tumor Cell 1 (TC 2) (highly cycling/metabolic). In TCGA-STAD (The Cancer Genome Atlas – Stomach Adenocarcinoma), high TC 1 scores associated with worse overall survival (P < 0.01), whereas TC 2 showed a nonsignificant trend. The stroma comprised nine populations; tumors were enriched for RGS5⁺ SMCs and FAP⁺ fibroblasts, with depletion of homeostatic PI16⁺ fibroblasts. Pseudotime traced a PI16⁺→CCL11⁺→PDGFRA⁺→FAP⁺ continuum featuring late NF-κB/STAT activation and extracellular matrix (ECM)-remodeling; SMCs rewired from contractile MYH11⁺ to angiocrine RGS5⁺ states. Ligand-receptor analysis indicated asymmetric tumor-stroma crosstalk: TC 1 preferentially engaged vaso-regulatory/EGFR–immune signaling to activate CAFs and SMCs, while TC 2 amplified PDGF/MDK growth-factor circuits; stromal feedback via WNT/NRG/HGF/TGF-β reinforced malignant programs. Spatial maps confirmed EPCAM-high tumor nests encased by COL1A2/FAP⁺ fibroblastic shells interwoven with ACTA2/RGS5⁺ strands.

Conclusion

This study highlights the critical role of CAFs and SMCs heterogeneity and their interactions within the GC TME (Tumor microenvironment). Targeting stromal pathways such as PDGF, TGF-β, and NF-κB signaling, immunomodulating CAFs, and disrupting SMC-derived vascular niches may improve therapeutic responses. Further experimental validation of ligand-receptor pairs and spatial determinants is warranted.

目的：本研究旨在探讨胃癌（GC）中癌相关成纤维细胞（CAFs）和平滑肌细胞（SMCs）的异质性及其与恶性上皮的相互作用，以寻找潜在的治疗靶点。方法：我们进行了多组学分析，整合了单细胞RNA测序和空间转录组学，辅以轨迹推断、调节子活性作图、配体-受体相互作用建模和外部队列的生存关联。结果：出现了两个恶性上皮程序-肿瘤细胞1 (TC 1)（伤口愈合/增殖）和肿瘤细胞1 (TC 2)（高循环/代谢）。在TCGA-STAD（癌症基因组图谱-胃腺癌）中，高TC 1评分与较差的总生存相关（P < 0.01），而TC 2无显著趋势。基质有9个居群；肿瘤中RGS5 + SMCs和FAP +成纤维细胞富集，而稳态PI16 +成纤维细胞缺失。伪时间追踪到一个PI16 +→CCL11 +→PDGFRA +→FAP +连续体，具有NF-κB/STAT晚期活化和细胞外基质（ECM）重塑的特征；SMCs从收缩的MYH11 +重新连接到血管分泌的RGS5 +状态。配体-受体分析显示不对称肿瘤-基质串串：TC 1优先参与血管调节/ egfr免疫信号激活CAFs和SMCs，而TC 2放大PDGF/MDK生长因子回路；通过WNT/NRG/HGF/TGF-β强化恶性程序的间质反馈。空间图证实epcam -高肿瘤巢由COL1A2/FAP +成纤维外壳和ACTA2/RGS5 +链交织而成。结论：本研究强调了CAFs和SMCs异质性及其在肿瘤微环境中的相互作用的关键作用。靶向间质通路如PDGF、TGF-β和NF-κB信号、免疫调节CAFs和破坏smc来源的血管壁龛可能会改善治疗反应。进一步的实验验证配体受体对和空间决定因素是必要的。

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引用次数: 0

Serine/threonine kinase 32 family proteins: The potential multifaceted regulators in cancer 丝氨酸/苏氨酸激酶32家族蛋白：癌症中潜在的多方面调节因子

IF 5 2区医学 Q2 Medicine

Translational Oncology

Pub Date : 2025-11-22 DOI: 10.1016/j.tranon.2025.102608

Longqiao Liu , Yuan Feng , Yang Liu , Lin Cheng , Peng Cheng

As a subgroup of AGC kinases, serine/threonine kinase 32 family (STK32, also known as Yet Another Novel Kinases family) consists of three members: STK32A, STK32B and STK32C. Recently, emerging evidences have implicated the aberrant expression and dysregulated functions of STK32 kinases in human malignancies. However, there is a lack of systematic review on this topic. Here, we aim to detailly examine the expression and functional features of STK32 family kinases within the context of present reports and public datasets related, and outline current understanding on the multifunctional roles and up-stream regulatory mechanisms and down-stream effectors of STK32 kinases to highlight key research focus for future exploration and provide rationale for developing STK32-targeted therapeutics in cancer.

丝氨酸/苏氨酸激酶32家族（STK32，又称Yet Another Novel kinases家族）是AGC激酶的一个亚群，由STK32A、STK32B和STK32C三个成员组成。近年来，越来越多的证据表明STK32激酶在人类恶性肿瘤中的异常表达和功能失调。然而，关于这一主题，目前还缺乏系统的综述。在此，我们的目标是在现有报告和相关公共数据集的背景下详细研究STK32家族激酶的表达和功能特征，并概述目前对STK32激酶的多功能作用、上游调控机制和下游效应物的了解，以突出未来探索的重点研究重点，并为开发STK32靶向癌症治疗提供依据。

引用次数: 0

B2M regulates ELANE in pyroptosis to affect pancreatic cancer progression B2M调节ELANE在胰腺癌焦亡中的作用

IF 5 2区医学 Q2 Medicine

Translational Oncology

Pub Date : 2025-11-21 DOI: 10.1016/j.tranon.2025.102613

Hui xie , Xiaonan Hu , Yongde Cai , Sheng Zhu , Zuliang Deng

The role of pyroptosis in pancreatic cancer remains controversial. Using two-sample Mendelian randomization (MR) integrating GWAS data from FinnGen (314,193 controls, 731 cases), pQTL data from Iceland, and the UK Biobank, we systematically investigated causal links between pyroptosis genes and pancreatic cancer. We found that Beta-2-microglobulin (B2M) indirectly increases pancreatic cancer risk by upregulating Neutrophil Elastase (ELANE)—to our knowledge, this is the first study to establish a causal, mediation-based genetic link between B2M and ELANE in the context of pancreatic cancer. Mediation analysis revealed ELANE accounts for 20.572 % [15.32%–25.81 %] of this effect. Sensitivity analyses confirmed robustness without significant pleiotropy, and bioinformatics validation supported our MR findings. Drug sensitivity analysis further identified potential therapeutic agents. The findings support B2M as a diagnostic biomarker for pancreatic cancer, given its significant overexpression in tumors and high diagnostic accuracy (AUC = 0.976, 95 % CI: 0.958–0.993), and highlight the B2M–ELANE axis—identified through a data-driven MR mediation framework—as a promising therapeutic target.

焦亡在胰腺癌中的作用仍有争议。采用两样本孟德尔随机化（MR），结合FinnGen的GWAS数据（314,193例对照，731例病例）、冰岛的pQTL数据和UK Biobank的pQTL数据，我们系统地研究了热亡基因与胰腺癌之间的因果关系。我们发现β -2微球蛋白（B2M）通过上调中性粒细胞弹性酶（ELANE）间接增加胰腺癌风险，据我们所知，这是第一个在胰腺癌背景下建立B2M和ELANE之间因果、基于介导的遗传联系的研究。中介分析显示，ELANE占20.572%[15.32% - 25.81%]。敏感性分析证实了鲁棒性，没有显著的多效性，生物信息学验证支持我们的MR发现。药物敏感性分析进一步确定了潜在的治疗药物。鉴于B2M在肿瘤中的显著过表达和高诊断准确性（AUC = 0.976, 95% CI: 0.958-0.993），该研究结果支持B2M作为胰腺癌的诊断生物标志物，并强调B2M - elane轴（通过数据驱动的MR中介框架确定）是一个有希望的治疗靶点。

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引用次数: 0

MMP11 promotes immune escape in esophageal carcinoma cells via the PD-L1/c-Myc signaling pathway MMP11通过PD-L1/c-Myc信号通路促进食管癌细胞的免疫逃逸。

IF 5 2区医学 Q2 Medicine

Translational Oncology

Pub Date : 2025-11-19 DOI: 10.1016/j.tranon.2025.102604

Shixing Li, Xuelei Lou, Zukuan Chang, Jinzhan Liu, Huilin Lu

Background

Esophageal cancer (ESCA) remains difficult to treat with surgery and chemotherapy showing limited impact on patient prognosis. Matrix metalloproteinase 11 (MMP11) has been linked to tumor progression and immune microenvironment modulation. This study explored MMP11′s role in regulating the PD-L1/c-Myc pathway in ESCA.

Methods

MMP11 expression was analyzed in ESCA tissues and cell lines using real-time PCR and western blot. Kaplan-Meier survival curves assessed the relationship between MMP11 expression and patient survival. Functional assays, including wound healing and flow cytometry, were conducted to examine ESCA cell migration and apoptosis.

Results

MMP11 silencing reduced PD-L1 expression and inhibited cell migration, while promoting apoptosis. It also decreased the protein levels of c-Myc pathway-related proteins. Co-culturing MMP11-depleted ESCA cells with PBMCs altered T regulatory cell subsets and increased immunostimulatory cytokine levels. In vivo, MMP11 knockdown suppressed tumor growth, Ki-67 expression, and the PD-L1/c-Myc signaling pathway.

Conclusion

These findings suggest that MMP11 activates the PD-L1/c-Myc pathway, contributing to immune evasion and ESCA progression. Targeting MMP11 could thus serve as a potential therapeutic approach for ESCA immunotherapy.

背景：食管癌（ESCA）仍然难以通过手术和化疗治疗，对患者预后的影响有限。基质金属蛋白酶11 （MMP11）与肿瘤进展和免疫微环境调节有关。本研究探讨了MMP11在ESCA中调控PD-L1/c-Myc通路中的作用。方法：采用实时荧光定量PCR和western blot检测ESCA组织和细胞系中MMP11的表达。Kaplan-Meier生存曲线评估MMP11表达与患者生存之间的关系。功能分析，包括伤口愈合和流式细胞术，检测ESCA细胞迁移和凋亡。结果：MMP11沉默可降低PD-L1表达，抑制细胞迁移，促进细胞凋亡。它还降低了c-Myc通路相关蛋白的蛋白水平。mmp11缺失的ESCA细胞与PBMCs共培养改变了T调节细胞亚群，增加了免疫刺激细胞因子水平。在体内，MMP11敲低抑制肿瘤生长、Ki-67表达和PD-L1/c-Myc信号通路。结论：这些发现提示MMP11激活PD-L1/c-Myc通路，促进免疫逃避和ESCA进展。因此，靶向MMP11可以作为ESCA免疫治疗的潜在治疗方法。

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