Translational Oncology最新文献

{"title":"A machine learning-based prognostic signature utilizing MSC proteomics for predicting bladder cancer prognosis and treatment response","authors":"Xinyu Zhang ,&nbsp;Pan Li ,&nbsp;Luhua Ji ,&nbsp;Yuanfeng Zhang,&nbsp;Ze Zhang,&nbsp;Yufeng Guo,&nbsp;Luyang Zhang,&nbsp;Suoshi Jing,&nbsp;Zhilong Dong,&nbsp;Junqiang Tian,&nbsp;Li Yang,&nbsp;Hui Ding,&nbsp;Enguang Yang,&nbsp;Zhiping Wang","doi":"10.1016/j.tranon.2025.102349","DOIUrl":"10.1016/j.tranon.2025.102349","url":null,"abstract":"<div><h3>Background</h3><div>Mesenchymal stem cells (MSCs), due to their tumor-targeting homing properties, are present in the tumor microenvironment (TME) and influence the biological behaviors of tumors. The purpose of this paper is to establish a signature based on the MSC secretome to predict the prognosis and treatment of bladder cancer (BLCA).</div></div><div><h3>Methods</h3><div>The presence of MSCs in BLCA was validated through flow cytometry and multiplex fluorescence immunohistochemistry (mFIHC), and the relationships between MSCs and clinical characteristics were explored. Unsupervised clustering analysis was performed on BLCA according to the differential proteins detected in MSC-conditioned medium (MSC<img>CM) using a cytokine array. Using the TCGA-BLCA, GSE32548, and GSE32894 datasets as background data, a risk signature was constructed according to the differential proteins in MSC<img>CM through machine learning. For the risk groups with high and low prognoses, we calculated Kaplan-Meier (K-M) curves. Additionally, we explored the relationships between the signature and the tumor immune landscape, response to immunotherapy, and chemotherapy drugs.</div></div><div><h3>Results</h3><div>Both flow cytometry and mFIHC confirmed the presence of MSCs in bladder tumors, and clinical samples revealed correlations between MSCs and the pathological grade, T stage, and Ki67 in BLCA. Based on differential proteins and unsupervised clustering analysis, BLCA patients were divided into two groups, and significant differences were found between these groups in terms of TME, immune response, and clinical treatments. Using machine learning, a signature was constructed with the combination algorithm Stepcox (both) + plsRcox, revealing significant survival differences between the high- and low-risk MSC groups. Regression analyses, along with ROC curves, further demonstrated that risk score independently predict the prognosis of patients with high predictive performance. Moreover, there were notable differences between the high- and low-risk groups in terms of the TME scores, immune infiltration, and immune checkpoints. For BLCA immunotherapy, the low-risk group suggested better efficacy, while conventional chemotherapy drugs such as gemcitabine and cisplatin might be less effective in the low-risk group.</div></div><div><h3>Conclusion</h3><div>The signature based on MSC secreted protein profiles could effectively predict the prognosis of BLCA and provided valuable guidance for treatment and drug resistance.</div></div>","PeriodicalId":48975,"journal":{"name":"Translational Oncology","volume":"54 ","pages":"Article 102349"},"PeriodicalIF":5.0,"publicationDate":"2025-03-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143591652","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Single-cell insights into HNSCC tumor heterogeneity and programmed cell death pathways","authors":"Yuanhao Chai ,&nbsp;Jianlin Zhang ,&nbsp;Wenwen Shao ,&nbsp;Ziwei Zhang","doi":"10.1016/j.tranon.2025.102341","DOIUrl":"10.1016/j.tranon.2025.102341","url":null,"abstract":"<div><h3>Background</h3><div>Head and neck squamous cell carcinoma (HNSCC) is a prevalent malignancy often diagnosed in advanced stages. Despite advancements in therapy, it retains a high mortality rate and significant recurrence risk. This study utilizes single-cell sequencing (scRNA-seq) to unravel HNSCC's complexity, identify therapeutic targets, and refine prognostic models.</div></div><div><h3>Methods</h3><div>Pseudotime trajectory and stemness analyses were performed on HNSCC tumor subpopulations, focusing on the C2 <em>MALAT1</em>+ Tumors subpopulation, which had the lowest CytoTRACE Score and represented the Lineage 2 endpoint in Slingshot analysis. The study examined programmed death and metabolic pathways in each subpopulation and developed a novel prognostic model using LASSO regression.</div></div><div><h3>Results</h3><div>The C2 <em>MALAT1</em>+ Tumors subpopulation exhibited reduced expression of programmed death pathways (e.g., Entotic cell death, Apoptosis, Pyroptosis) and metabolic pathways (e.g., Riboflavin metabolism, Glycolysis/Gluconeogenesis). Key transcription factors included LEF1, RFX3, CREM, MZF1, and ZNF202. Prognostic models based on the <em>MALAT1</em> Tumors Risk Score (MTRS) revealed worse survival and higher tumor purity in the high MTRS group. Risk genes included <em>ADM, RPL31, EIF5B</em>, and <em>TAF7</em>. Additionally, activated CD4 memory T cells were enriched in the high MTRS group, which also showed greater sensitivity to Cisplatin, Docetaxel, and Paclitaxel.</div></div><div><h3>Conclusions</h3><div>ScRNA-seq revealed the heterogeneity of HNSCC subpopulations, highlighting the unique features of the C2 <em>MALAT1</em>+ Tumors subpopulation. This study identified novel prognostic markers and therapeutic targets, offering insights into HNSCC progression, drug resistance, and potential treatments.</div></div>","PeriodicalId":48975,"journal":{"name":"Translational Oncology","volume":"54 ","pages":"Article 102341"},"PeriodicalIF":5.0,"publicationDate":"2025-03-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143579646","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Tumor-stroma proportion is associated with increased M2 macrophage abundance and predicts the resistance to immune checkpoint blockade in breast cancer","authors":"Yincheng Liu ,&nbsp;Ningyi Xue ,&nbsp;Yuelin Liu ,&nbsp;Jie Mei ,&nbsp;Yun Cai ,&nbsp;Zhenghui Wang ,&nbsp;Hongxin Lin ,&nbsp;Mengyun Wan ,&nbsp;Ji Zhou ,&nbsp;Tiansong Xia ,&nbsp;Yichao Zhu ,&nbsp;Shui Wang","doi":"10.1016/j.tranon.2025.102343","DOIUrl":"10.1016/j.tranon.2025.102343","url":null,"abstract":"<div><h3>Background</h3><div>The tumor stroma has been reported to be associated with worse prognosis in several solid tumors, but its prognostic value in breast cancer (BRCA) is still undefined.</div></div><div><h3>Methods</h3><div>In this research, multiple public and in-house patient cohorts were collected to demonstrate the clinical and immune correlations of tumor-stroma proportion (TSP) in BRCA. In addition, <em>in vitro</em> assays uncovered the oncogenic role of TSP-related collagen in BRCA.</div></div><div><h3>Results</h3><div>High TSP status based on hematoxylin and eosin (HE) staining was associated with positive hormone receptor status, advanced clinical stages, and poor immune checkpoint blockade (ICB) response. In addition, we developed a RNA-sequencing (RNA-seq)-based stromal score based on four critical genes expression (AEBP1, COL6A3, CTSK, and PLAC9). Both TSP status and stromal score were positively associated with increased M2 macrophage abundance in BRCA. Moreover, tumor collagen has been found to be enriched in samples with the high TSP status, and collagen promoted BRCA cells aggressiveness and macrophage M2 polarization.</div></div><div><h3>Conclusions</h3><div>The tumor stroma was found to be notably related to poor ICB response in patients with BRCA as a result of tumor stroma-macrophage interactions. Thus, the TSP status could predict the clinical outcomes of BRCA patients receiving ICB therapy.</div></div>","PeriodicalId":48975,"journal":{"name":"Translational Oncology","volume":"54 ","pages":"Article 102343"},"PeriodicalIF":5.0,"publicationDate":"2025-03-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143579647","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Comprehensive assessment of serum 3′-tRFArg as a novel diagnostic biomarker for gastric cancer","authors":"Rui Ding ,&nbsp;Yang Li ,&nbsp;Yu Zhang ,&nbsp;Xun Li ,&nbsp;Yunjian Song ,&nbsp;Xinliang Gu ,&nbsp;Xianjuan Shen ,&nbsp;Shaoqing Ju","doi":"10.1016/j.tranon.2025.102338","DOIUrl":"10.1016/j.tranon.2025.102338","url":null,"abstract":"<div><div>Gastric cancer is one of the malignant tumors with the highest morbidity and mortality rates worldwide. Yet, there is a lack of diagnostic markers with high sensitivity in the clinic. tRNA-derived small RNAs are a novel type of non-coding small RNAs, which are abundant in tumor cells and body fluids. In this study, we explored the potential of 3′-tRF^Arg as a tumor marker for the diagnosis of GC. Differential expression of 3′-tRF^Arg was screened by high-throughput sequencing, and Quantitative real-time PCR confirmed its low expression in GC serum with good stability. Differential expression of serum 3′-tRF^Arg could distinguish between GC patients, gastritis patients, and healthy donors and was significantly correlated with clinical pathological features such as tumor differentiation, lymph node metastasis, and TNM staging. The receiver operating characteristic curve showed that 3′-tRF^Arg had a higher diagnostic value compared with conventional biomarkers, especially in the diagnosis of early gastric cancer. In conclusion, our results suggest that 3′-tRF^Arg can serve as a highly sensitive biomarker with a certain value for monitoring tumor development and prognosis.</div></div>","PeriodicalId":48975,"journal":{"name":"Translational Oncology","volume":"54 ","pages":"Article 102338"},"PeriodicalIF":5.0,"publicationDate":"2025-03-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143580306","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Immunomodulation on tumor immune microenvironment in acquired targeted therapy resistance and implication for immunotherapy resistance","authors":"Ming-Yu Chou ,&nbsp;Muh-Hwa Yang","doi":"10.1016/j.tranon.2025.102353","DOIUrl":"10.1016/j.tranon.2025.102353","url":null,"abstract":"<div><div>The emergence of molecularly targeted therapies and immunotherapies has revolutionized cancer treatment, yet the optimal sequencing of these modalities remains debated. While targeted therapies often induce initial immunostimulatory effects, the development of resistance is accompanied by dynamic alterations in the tumor-immune microenvironment. These changes can promote tumor growth, hinder immune surveillance, and contribute to subsequent immunotherapy resistance. This review focuses on solid tumors and summarizes the immunomodulatory effects arising in the context of targeted therapy resistance, highlighting the challenges they pose for the subsequent immunotherapy efficacy.</div></div>","PeriodicalId":48975,"journal":{"name":"Translational Oncology","volume":"54 ","pages":"Article 102353"},"PeriodicalIF":5.0,"publicationDate":"2025-03-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143579648","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"The pancreatitis-cancer transformation-related factor, human rhomboid family-1, promotes pancreatic cancer progression through the SRC/YAP signaling pathway","authors":"Zhilong Ma ,&nbsp;Jie Hua ,&nbsp;Miaoyan Wei ,&nbsp;Lin Han ,&nbsp;Mingwei Dong ,&nbsp;Wangcheng Xie ,&nbsp;Tingyi Luo ,&nbsp;Qingcai Meng ,&nbsp;Wei Wang ,&nbsp;Zhenshun Song ,&nbsp;Si Shi ,&nbsp;Xianjun Yu ,&nbsp;Jin Xu","doi":"10.1016/j.tranon.2025.102346","DOIUrl":"10.1016/j.tranon.2025.102346","url":null,"abstract":"<div><div>Pancreatic cancer is an aggressive malignancy characterized by rapid progression, unfavorable outcomes, and a low early detection rate. Elucidating the mechanisms underlying the onset and progression of pancreatic tumors is essential for early detection and for developing preventive measures. Even though human rhomboid family-1 (RHBDF) acts as an oncogene in various tumors, the role of RHBDF in pancreatic cancer progression remains unexplored. Here, publicly available datasets, including samples of chronic pancreatitis associated with pancreatic cancer from our center, were used for bioinformatics analyses, including differential expression, survival, and enrichment studies. The findings were validated by immunohistochemical staining and in vitro experiments. We found that RHBDF1 was significantly upregulated in tumor samples relative to adjacent non-tumor and pancreatitis tissues, and its expression increased in correlation with the progression of pancreatitis to cancer. Furthermore, RHBDF1 promoted the proliferation, migration, and invasion of pancreatic cancer cells, and in vivo studies demonstrated that RHBDF1 promoted pancreatic cancer progression, tissue fibrosis, and the formation of new blood vessels. RNA-sequencing and cell functional experiments indicated that RHBDF1 promotes the progression of pancreatic cancer through the SRC-YAP signaling pathway. In summary, the pancreatitis-cancer transformation-related factor, RHBDF1, promotes pancreatic cancer progression by activating the SRC-YAP signaling cascade, indicating that RHBDF1 could be a viable target for the diagnosis and treatment of early-stage pancreatic cancer.</div></div>","PeriodicalId":48975,"journal":{"name":"Translational Oncology","volume":"54 ","pages":"Article 102346"},"PeriodicalIF":5.0,"publicationDate":"2025-03-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143580305","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"BUB1B promotes cisplatin resistance in gastric cancer via Rad51-mediated DNA damage repair","authors":"Zhe Qin ,&nbsp;Fangzhou Ye ,&nbsp;Jiayi Wang,&nbsp;Jun Jiang,&nbsp;Xiaohong Zhang,&nbsp;Huanqing Li,&nbsp;Li Feng","doi":"10.1016/j.tranon.2025.102334","DOIUrl":"10.1016/j.tranon.2025.102334","url":null,"abstract":"<div><h3>Background</h3><div>Cisplatin resistance significantly impedes the treatment of gastric cancer (GC). This work examined the possible therapeutic target status and function of <em>BUB1B</em> in controlling cisplatin resistance.</div></div><div><h3>Methods</h3><div>Following the identification of differentially expressed genes (DEGs), protein-protein interaction (PPI) network analysis was conducted using datasets from the Cancer Genome Atlas-stomach adenocarcinoma (TCGA-STAD), GSE51575, and GSE79973. Functional tests assessed the effect of <em>BUB1B</em> overexpression and knockdown on the GC cells. Enrichment analysis and RNA-seq identified pathways linked to <em>BUB1B</em>. Additionally, the function of <em>BUB1B</em> in GC cells resistant to cisplatin in regulating DNA repair was examined, as its relationship with Rad51 inhibitor (B02) in regulating cell cycle, proliferation, and apoptosis. The combined effects of <em>Rad51</em> suppression and <em>BUB1B</em> overexpression on tumor development in cisplatin-resistant GC cells were further validated <em>in vivo</em> xenograft models.</div></div><div><h3>Results</h3><div>Significant overexpression of six critical overlapping genes was seen in GC tissues. The GC cell invasion, migration, and proliferation processes were improved by <em>BUB1B</em> overexpression, whereas <em>BUB1B</em> knockdown prevented these outcomes. Genes involved in DNA repair were downregulated by <em>BUB1B</em> knockdown, according to an RNA-seq study. <em>BUB1B</em> overexpression boosted cell survival via modulating cell cycle proteins, but <em>BUB1B</em> knockdown hampered DNA repair and increased death in cisplatin-resistant GC cells. Overexpression of <em>BUB1B</em> enhanced tumor development <em>in vivo</em> and counteracted the inhibitory effects of B02 on cell growth.</div></div><div><h3>Conclusion</h3><div><em>BUB1B</em> enhances cisplatin resistance in gastric cancer by regulating DNA repair and cell cycle progression, suggesting that targeting <em>BUB1B</em> may be a feasible therapeutic strategy.</div></div>","PeriodicalId":48975,"journal":{"name":"Translational Oncology","volume":"54 ","pages":"Article 102334"},"PeriodicalIF":5.0,"publicationDate":"2025-03-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143563660","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Inflammasomes in lymphocytes as therapeutic targets","authors":"Zarema Albakova","doi":"10.1016/j.tranon.2025.102342","DOIUrl":"10.1016/j.tranon.2025.102342","url":null,"abstract":"<div><div>Inflammasomes are cytoplasmic macromolecular complexes playing an important role in sensing exogenous and endogenous stimuli. Inflammasome activation leads to IL-1β and IL-18 secretion and pyroptosis. The concept of non-self recognition triggering inflammasome activation has been well-established for myeloid cells. However, increasing evidence suggests the presence of functional inflammasome or inflammasome-related components in lymphocytes. Dysregulated expression of inflammasome contributes to the development of many diseases, including cardiovascular, infectious, neurodegenerative diseases and cancer. Multiple clinical trials are being conducted to assess drugs targeting various inflammasome components. This review discusses current knowledge on inflammasome activation in T, B and NK cells and explores their potential as therapeutic targets. Further understanding inflammasome and pyroptotic pathways in lymphocytes may have implications in the development of novel immunotherapeutic strategies.</div></div>","PeriodicalId":48975,"journal":{"name":"Translational Oncology","volume":"54 ","pages":"Article 102342"},"PeriodicalIF":5.0,"publicationDate":"2025-03-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143548887","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Targeting FEN1/EXO1 to enhance efficacy of PARP inhibition in triple-negative breast cancer","authors":"Mallory I. Frederick ,&nbsp;Elicia Fyle ,&nbsp;Anna Clouvel ,&nbsp;Djihane Abdesselam ,&nbsp;Saima Hassan","doi":"10.1016/j.tranon.2025.102337","DOIUrl":"10.1016/j.tranon.2025.102337","url":null,"abstract":"<div><div>Triple-negative breast cancer (TNBC) is the most aggressive subtype of breast cancer. The only targeted therapeutic approach that has emerged for early TNBC patients with BRCA-mutations (BRCA^MUT) are PARP inhibitors (PARPi). In combination, PARPi may benefit a larger cohort of TNBC patients. We used our previously identified 63-gene signature that was associated with PARPi response to identify candidate genes that could be therapeutic targets. We selected FEN1 for further investigation since its knockdown was associated with an increase in G2/M arrest, DNA damage, and apoptosis. We first tested LNT1, a FEN1/EXO1 inhibitor, in a panel of 10 TNBC cell lines. LNT1 sensitivity was identified predominantly in <em>BRCA1</em>-mutant/deficient cell lines. However, the combination of PARPi and LNT1 demonstrated a synergistic or additive effect in 7/10 cell lines, mainly in <em>BRCA1/2</em> wild-type (BRCA^WT) and <em>BRCA2</em>-mutant cell lines, with intrinsic and acquired resistance to PARPi. The greatest synergy was observed in a <em>BRCA2</em>-mutant cell line with acquired resistance to olaparib (HCC1395-OlaR), with a combination index value of 0.20. In the synergistic cell lines, BT549 (BRCA^WT) and HCC1395-OlaR, the combination was associated with a rapid progression in DNA replication fork speed, an early and sustained increase in DNA damage in comparison to each of the single-agents. However, in the additive BRCA1/2 wild-type cell lines, MDAMB231 and HCC1806, the combination demonstrated a high DNA damage response that was largely driven by either talazoparib or LNT1. Therefore, targeting FEN1/EXO1 with PARPi is a promising targeted combination approach, particularly in the context of PARPi-resistant and BRCA^WT TNBC.</div></div>","PeriodicalId":48975,"journal":{"name":"Translational Oncology","volume":"54 ","pages":"Article 102337"},"PeriodicalIF":5.0,"publicationDate":"2025-03-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143548886","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"TTC7A-ALK, a novel ALK fusion variant identified in a patient with metastatic lung adenocarcinoma, exhibits excellent response to crizotinib","authors":"Meijin Huang ,&nbsp;Xiangqing Zhu ,&nbsp;Wenmang Xu ,&nbsp;Jun Zhu ,&nbsp;Xin Xun ,&nbsp;Bin Su ,&nbsp;Hong Chen","doi":"10.1016/j.tranon.2025.102345","DOIUrl":"10.1016/j.tranon.2025.102345","url":null,"abstract":"<div><div>Non-small cell lung cancer (NSCLC) remains a leading cause of cancer-related mortality worldwide. <em>ALK</em> gene rearrangement has been identified in 3 % to 5 % of the patients with NSCLC. Thanks to the advancements in second-generation sequencing technology, an increasing number of novel fusion partners have been identified. In our research, we discovered a rare <em>ALK</em> fusion, <em>TTC7A-ALK</em>, in a patient with advanced lung adenocarcinoma using targeted next-generation sequencing (NGS). After being diagnosed with advanced lung adenocarcinoma with <em>TTC7A-ALK</em> fusion<em>,</em> the patient received crizotinib treatment and achieved a progression-free survival of 29 months. Additonanlly, we conducted further functional analyses on this fusion protein to assess its oncogenic potential. Similar to <em>EML4-ALK</em>, the <em>TTC7A-ALK</em> fusion protein can promote the growth of Ba/F3 cells under IL-3-independent conditions in vitro. In vivo studies demonstrate that the <em>TTC7A-ALK</em> fusion protein could enhance the tumorigenesis of NIH3T3 cells in nude mice, which can be suppressed by crizotinib. Mechanistic studies indicated that the ectopic expression of <em>TTC7A-ALK</em> in 293T cells led to the hyperactivation of downstream MAPK and PI3K/Akt pathways, which can be inhibited by crizotinib. Furthermore, upon tumor progression, the patient transitioned to alectinib, which provided rapid symptom relief and controlled the majority of lesions. Conclusionly, we identified and validated <em>TTC7A-ALK</em> as a oncogenic fusion in NSCLC. The patient demonstrated a significant clinical benefit from sequential treatment with crizotinib and alectinib, highlighting <em>TTC7A-ALK</em> as a novel therapeutic target for <em>ALK</em> inhibitors. These findings extend the spectrum of actionable <em>ALK</em> fusions and promote the inclusion of rare fusion detection in clinical diagnostic processes and treatment strategies.</div></div>","PeriodicalId":48975,"journal":{"name":"Translational Oncology","volume":"54 ","pages":"Article 102345"},"PeriodicalIF":5.0,"publicationDate":"2025-03-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143563588","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}