Translational Oncology最新文献

{"title":"In-depth patient-specific analysis of tumor heterogeneity in melanoma brain metastasis: Insights from spatial transcriptomics and multi-region bulk sequencing","authors":"Nidhi Sharma ,&nbsp;Jana Rájová ,&nbsp;Georgios Mermelekas ,&nbsp;Kim Thrane ,&nbsp;Joakim Lundeberg ,&nbsp;Alia Shamikh ,&nbsp;Sofi Vikström ,&nbsp;Haris Babačić ,&nbsp;Margret Jensdottir ,&nbsp;Janne Lehtiö ,&nbsp;Maria Pernemalm ,&nbsp;Hanna Eriksson","doi":"10.1016/j.tranon.2025.102468","DOIUrl":"10.1016/j.tranon.2025.102468","url":null,"abstract":"<div><div>Melanoma brain metastases (MBM) exhibit extensive intertumor and intratumor heterogeneity (ITH), driven by a complex tumor microenvironment. The aim of this study was to perform a detailed analysis of individual MBM patient tumors using a multiomics approach, integrating spatial transcriptomics with multi-region bulk exome, proteome, and transcriptome profiling for a small group of four patient samples. We identified significant patient-specific variations in immune cell infiltration, particularly in B/plasma cells, myeloid cells, and cancer-associated fibroblasts (CAFs). Notably, immunotherapy-treated patients showed enriched pathways related to epithelial-mesenchymal transition (EMT), interferon-gamma (IFN-γ) signaling, oxidative phosphorylation, T-cell signaling, inflammation and DNA damage, which aligned with distinct cellular compositions observed in the spatial analysis. We also uncovered considerable ITH, especially at the protein level, revealing differential expression patterns of key tumor and immune-related markers. The correlation between mRNA and protein data highlighted consistent enrichment of critical pathways across multiomics layers. These findings highlight the molecular and cellular landscape of individual patient MBM, underscoring the importance of addressing tumor heterogeneity in the development of effective therapeutic strategies.</div></div>","PeriodicalId":48975,"journal":{"name":"Translational Oncology","volume":"59 ","pages":"Article 102468"},"PeriodicalIF":5.0,"publicationDate":"2025-07-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144623461","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}

{"title":"Characterization and functional analysis of BRCA1 and BRCA2 variants in a cohort of 100 unselected patients undergoing germline screening","authors":"Qianqian Shi ,&nbsp;Jinshuang Gao ,&nbsp;Haiyang Yu ,&nbsp;Yaodong Niu ,&nbsp;Erfeng Yuan ,&nbsp;Yaqing Guo ,&nbsp;Liying Song ,&nbsp;Yang Fang ,&nbsp;Yu Wang ,&nbsp;Enwu Yuan ,&nbsp;Yanwu Zhang ,&nbsp;Xin Zhao ,&nbsp;Linlin Zhang","doi":"10.1016/j.tranon.2025.102471","DOIUrl":"10.1016/j.tranon.2025.102471","url":null,"abstract":"<div><div>Germline loss-of-function mutations in <em>BRCA1</em> and <em>BRCA2</em> (<em>BRCA</em>) genes are well-established as causative factors for hereditary breast and ovarian cancer (HBOC), conferring an approximately tenfold increased lifetime risk. The identification of <em>BRCA</em> mutations is essential for risk assessment and management in high-risk individuals and cancer patients. In this study, we utilized next-generation sequencing (NGS) to comprehensively analyze the entire coding regions of <em>BRCA</em> genes in a cohort of 100 unselected patients undergoing germline screening (average age ≤45 years and/or family history of related cancers). A total of twenty-two variants were identified, including thirteen pathogenic or likely pathogenic variants (PVs/LPVs) and nine variants of uncertain significance (VUSs). Notably, six novel variants (two in <em>BRCA1</em> and four in <em>BRCA2</em>) were discovered. Molecular subtyping revealed that breast cancer (BC) patients with <em>BRCA</em> variants were predominantly human epidermal growth factor receptor-2 (HER2)-negative. Using in silico prediction tools, nine VUSs were reclassified, with functional impairment confirmed for the <em>BRCA2</em> p.W2619C and <em>BRCA2</em> p.N1023_I1024del variants. Functional assays demonstrated that the <em>BRCA2</em> p.W2619C variant significantly enhanced cell proliferation, migration, and invasion. Moreover, cells harboring the <em>BRCA2</em> p.W2619C mutation exhibited increased sensitivity to Olaparib, suggesting potential therapeutic benefit from PARP inhibitors for patients with this variant. Our study identified six novel <em>BRCA</em> mutations and functionally validated the pathogenicity of the <em>BRCA2</em> p.W2619C variant, thereby advancing the understanding of <em>BRCA</em>-related cancer risk and supporting enhanced genetic counseling and testing strategies for at-risk populations.</div></div>","PeriodicalId":48975,"journal":{"name":"Translational Oncology","volume":"59 ","pages":"Article 102471"},"PeriodicalIF":5.0,"publicationDate":"2025-07-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144623465","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}

{"title":"Systemic and tumor-specific inflammatory markers VCAM-1 and ICAM-1 as indicators of extent of surgery and oncologic outcome in advanced ovarian cancer","authors":"Okan Gultekin ,&nbsp;Jordi Gonzalez-Molina ,&nbsp;Dhifaf Sarhan ,&nbsp;Nina Groes-Kofoed ,&nbsp;Mahmood Ul Hassan ,&nbsp;Kaisa Lehti ,&nbsp;Sahar Salehi","doi":"10.1016/j.tranon.2025.102462","DOIUrl":"10.1016/j.tranon.2025.102462","url":null,"abstract":"&lt;div&gt;&lt;h3&gt;Background&lt;/h3&gt;&lt;div&gt;Cytoreductive surgery in advanced ovarian cancer presents significant challenges and there is a need for an improved patient selection to surgical treatment. Cytokines and adhesion molecules are key regulators of immune responses, playing crucial roles in tumor cell adhesion, metastasis, and immune evasion. They shape the tumor microenvironment and influence systemic immunity, ultimately affecting cancer progression. Despite their recognized significance in cancer biology, the potential of cytokines as predictive biomarkers for surgical complexity and recurrence in ovarian cancer remains insufficiently characterized. This study aimed to elucidate the correlation between inflammatory cytokines and surgical outcomes, to identify reliable liquid or tissue-based biomarkers that could enhance patient stratification and support preoperative decision-making in ovarian cancer management.&lt;/div&gt;&lt;/div&gt;&lt;div&gt;&lt;h3&gt;Methods&lt;/h3&gt;&lt;div&gt;The Concentration of 10 inflammatory cytokines and 2 adhesion molecules concentrations were measured by Luminex based assay in blood, tumor tissue, and ascitic fluid samples from patients with advanced ovarian cancer prior to cytoreductive surgery. Clinical data were prospectively collected. Correlations between cytokines and adhesion molecules levels and surgical complexity, as well as disease/cancer recurrence, were assessed using Pearson two-tail statistical test analyses. The association between adhesion molecules and surgical extent, and recurrence was analysed using logistic regression yielding odds ratios (OR) with 95 % confidence intervals, adjusted for relevant covariates. The diagnostic accuracy of biomarker candidates was evaluated using receiver operating characteristic (ROC) curve analysis&lt;/div&gt;&lt;/div&gt;&lt;div&gt;&lt;h3&gt;Results&lt;/h3&gt;&lt;div&gt;In blood, higher VCAM-1 and ICAM-1 levels correlated with lower surgical complexity scores, while ascitic VCAM-1 was linked to longer surgical durations. CXCL-12 in tumor and IL-32 in ascites were positively correlated with increased surgery duration, indicating their role in systemic inflammation. Elevated VCAM-1 and ICAM-1 levels in tumor tissue were strongly associated with increased cancer recurrence risk, suggesting their involvement in metastasis and immune evasion. Traditional preoperative markers, including albumin and CRP, did not correlate significantly with surgical complexity, highlighting the need for novel biomarkers. In the adjusted multivariable regression model, VCAM-1 in blood was associated with recurrence, OR 10.1 (95 % CI, 1.30-77.8; &lt;em&gt;p&lt;/em&gt;=0.027). Similarly, VCAM-1 in blood demonstrated exceptional predictive capability, Area Under Curve=0.886 with cutoff point of 0.696.&lt;/div&gt;&lt;/div&gt;&lt;div&gt;&lt;h3&gt;Conclusions&lt;/h3&gt;&lt;div&gt;Inflammatory markers can serve as valuable predictors of surgical complexity and recurrence in advanced ovarian cancer. Particularly the levels of VCAM-1 in blood was identified as a potential predictive marker to be tested in adequately p","PeriodicalId":48975,"journal":{"name":"Translational Oncology","volume":"59 ","pages":"Article 102462"},"PeriodicalIF":5.0,"publicationDate":"2025-07-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144611878","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}

{"title":"Mitochondrial apoptosis induced by MNAT1 in laryngeal squamous cell carcinoma cells reverses drug resistance","authors":"Ran An ,&nbsp;Fan Yang ,&nbsp;Yujian Teng ,&nbsp;Yan Guo ,&nbsp;Rui Zhao ,&nbsp;Jing Cao ,&nbsp;Yaohui Liu ,&nbsp;Yue Wang ,&nbsp;Pengyan Liu ,&nbsp;Ming Liu ,&nbsp;Linli Tian","doi":"10.1016/j.tranon.2025.102460","DOIUrl":"10.1016/j.tranon.2025.102460","url":null,"abstract":"<div><h3>Background</h3><div>Laryngeal squamous cell carcinoma (LSCC), the predominant histological subtype of laryngeal cancer with a poor diagnosis, requires further exploration of its molecular mechanisms and potential therapeutic targets.</div></div><div><h3>Methods</h3><div>The expression of MNAT1 in LSCC was detected by western blotting and IHC. EDU analysis, colony formation assay, scratch assay, transwell assay and flow cytometry were used to detect cell proliferation, migration, invasion and apoptosis. The downstream genes of MNAT1 were predicted by RNA-seq. The interaction between MNAT1 and GDF15 was verified by Co-immunoprecipitation assay. The effect of MNAT1 on mitochondrial activity in LSCC cells was determined by ROS, JC-1, and lysosomal mitochondrial activity. The effect of MNAT1 and GDF15 on tumor growth of drug-resistant cells was evaluated in vivo.</div></div><div><h3>Results</h3><div>MNAT1 was highly expressed in LSCC tissues. After MNAT1-knockdown, the proliferation, migration and invasion of LSCC cells were inhibited, the level of apoptosis was significantly increased, and the resistance to cisplatin was decreased. MNAT1 interacts with GDF15. MNAT1 affects cell proliferation, migration and invasion through GDF15, and further affects mitochondrial apoptosis through AMPK pathway. In addition, MNAT1-knockdown and GDF15-knockdown reduced the tumor growth rate and enhanced the sensitivity of cisplatin in vivo.</div></div><div><h3>Conclusions</h3><div>MNAT1 promoted GDF15-mediated changes in AMPK pathway to affect mitochondrial apoptosis, which reveals the progression of LSCC and the mechanism of chemotherapy resistance, providing a new understanding of the mechanism of mitochondrial apoptosis and chemotherapy resistance in LSCC.</div></div>","PeriodicalId":48975,"journal":{"name":"Translational Oncology","volume":"59 ","pages":"Article 102460"},"PeriodicalIF":5.0,"publicationDate":"2025-07-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144595417","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}

{"title":"Integrated single-cell sequencing for the development of a GJA4-based precision immuno-prognostic model in melanoma","authors":"Yantao Ding ,&nbsp;Si Xie ,&nbsp;Wenyang Nie ,&nbsp;Yun Bai ,&nbsp;Tianyu Yao ,&nbsp;Yixiao Wang ,&nbsp;Jiajie Chen ,&nbsp;Bo Liang ,&nbsp;Yi Zhou ,&nbsp;Hui Cheng ,&nbsp;Zaixing Wang ,&nbsp;Shengxiu Liu","doi":"10.1016/j.tranon.2025.102450","DOIUrl":"10.1016/j.tranon.2025.102450","url":null,"abstract":"<div><h3>Methods</h3><div>We conducted an analysis of RNA-seq and microarray data obtained from the TCGA and GEO databases, alongside single-cell RNA sequencing (scRNA-seq) data from glioma patients within the GEO repository. This comprehensive investigation, augmented by experimental studies, concentrated on exploring the interactions between tumor-associated endothelial cells (TECs) and tumors, as well as elucidating the molecular mechanisms involved.</div></div><div><h3>Results</h3><div>Single-cell sequencing analysis identified differentially expressed genes within tumor-associated endothelial cells. Further investigation highlighted GJA4 as a pivotal marker gene for a terminal subpopulation, with its expression linked to poor prognosis. Subsequent experiments were conducted to explore its underlying functional mechanisms.</div></div><div><h3>Conclusions</h3><div>GJA4 is highly expressed in melanoma patients, and its differential expression in tumor-associated endothelial cells influences melanoma proliferation and migration. GJA4-based risk models hold potential as predictive and therapeutic targets for personalized melanoma treatment.</div></div>","PeriodicalId":48975,"journal":{"name":"Translational Oncology","volume":"59 ","pages":"Article 102450"},"PeriodicalIF":5.0,"publicationDate":"2025-07-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144587792","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}

{"title":"Novel multi-omics analysis revealing metabolic heterogeneity of breast cancer cell and subsequent development of associated prognostic signature","authors":"Peng Zhang ,&nbsp;Cuicui Li ,&nbsp;Fen Li ,&nbsp;Jiezhong Wu ,&nbsp;Kunpeng Hu ,&nbsp;He Huang","doi":"10.1016/j.tranon.2025.102444","DOIUrl":"10.1016/j.tranon.2025.102444","url":null,"abstract":"<div><h3>Background</h3><div>Breast cancer remains one of the most prevalent malignancies globally, with metabolic reprogramming contributing significantly to tumor progression, immune evasion, and treatment resistance. Understanding the metabolic heterogeneity and its interaction with the tumor microenvironment is crucial for improving prognostic predictions and therapeutic strategies.</div></div><div><h3>Methods</h3><div>We integrated single-cell RNA sequencing (scRNA-seq), bulk RNA sequencing, and clinical data to characterize metabolic patterns in breast cancer. Immunoregulatory genes were obtained from the TISIDB database and analyzed by weighted gene co-expression network analysis (WGCNA) to identify key metabolic-related modules and hub genes. A metabolic risk signature was constructed using machine learning algorithms. Immune cell infiltration and immune checkpoint profiles were assessed to explore tumor microenvironment differences. Drug sensitivity prediction was performed via the OncoPredict tool. Functional assays investigated the oncogenic role of PDCD1 in breast cancer cell lines.</div></div><div><h3>Results</h3><div>We identified distinct breast cancer epithelial subpopulations with highly activated glycolysis and associated metabolic pathways. Two patient clusters showed significant prognostic differences; the cluster with elevated glycolytic activity exhibited increased immune suppression, higher M2 macrophage infiltration, and poorer survival outcomes. The metabolic risk signature demonstrated robust prognostic power across multiple cohorts. High-risk patients displayed increased immune suppressive markers and reduced chemotherapy sensitivity. PDCD1 knockdown experiments confirmed its role in promoting proliferation, migration, and invasion of breast cancer cells.</div></div><div><h3>Conclusions</h3><div>Our study reveals metabolic heterogeneity linked to glycolytic reprogramming and immune modulation in breast cancer. The established metabolic signature offers a powerful prognostic tool and identifies potential therapeutic targets such as PDCD1. These findings contribute to precision oncology by guiding tailored treatment strategies based on metabolic and immune profiles.</div></div>","PeriodicalId":48975,"journal":{"name":"Translational Oncology","volume":"59 ","pages":"Article 102444"},"PeriodicalIF":5.0,"publicationDate":"2025-07-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144580060","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}

{"title":"Sitravatinib combined with venetoclax exerts effective synergy to eliminate acute myeloid leukemia cells with FLT3-ITD mutations","authors":"Jie Yang ,&nbsp;Yvyin Zhang ,&nbsp;Qingshan Li ,&nbsp;Peihong Wang","doi":"10.1016/j.tranon.2025.102467","DOIUrl":"10.1016/j.tranon.2025.102467","url":null,"abstract":"<div><div>We have previously identified sitravatinib as a potent inhibitor of FLT3, capable of overcoming resistance to gilteritinib in the treatment of acute myeloid leukemia (AML). The combination of venetoclax and FLT3 inhibitors gilteritinib and quizartinib has shown promising results in reducing leukemia burden and improving survival in pre-clinical studies and clinical trials of AML with FLT3 mutation. In this study, we aimed to investigate the therapeutic effect of treating AML with sitravatinib combined with venetoclax. Our findings indicated that the combination of sitravatinib and venetoclax significantly decreased cell viability and increased cell apoptosis in AML cell lines harboring FLT3 mutation, more so than either treatment alone. These two agents exerted strong synergistic effects in FLT3-ITD AML cell lines and patient bone marrow cells in vitro. The activation of MAPK/ERK signaling are common causes that weaken the efficacy of FLT3 inhibitors, while the upregulation of anti-apoptotic proteins including BCL-xL and MCL-1 leads to venetoclax resistance. Our data demonstrated that sitravatinib plus venetoclax further suppressed the phosphorylation of AKT and ERK as well as downregulated MCL-1 and BCL-xL, which mechanically explain the synergistic effect. Finally, we tested the potential application of sitravatinib plus venetoclax in vivo using patient-derived xenografts, and found that the combined therapy was significantly more effective in inhibiting leukemia cell expansion, reducing infiltration in the spleen, and prolonging survival time compared to a single administration. Our study demonstrates the potential use of sitravatinib plus venetoclax as an alternative therapeutic strategy to treat AML patients with FLT3-ITD mutation.</div></div>","PeriodicalId":48975,"journal":{"name":"Translational Oncology","volume":"59 ","pages":"Article 102467"},"PeriodicalIF":5.0,"publicationDate":"2025-07-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144572416","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}

{"title":"Differential gene expression profiles of pancreatic ductal adenocarcinomas among African American and caucasian American patients","authors":"Prachi Bajpai ,&nbsp;Ravi Paluri ,&nbsp;Sameer Al Diffalha ,&nbsp;Darshan S Chandrashekar ,&nbsp;Farrukh Afaq ,&nbsp;Dennis Otali ,&nbsp;Amr Elkholy ,&nbsp;C. Ryan Miller ,&nbsp;Shajan Peter ,&nbsp;Ashish Manne ,&nbsp;Ganji Purnachandra Nagaraju ,&nbsp;Madhu Sudhana Saddala ,&nbsp;Moh’d Khushman ,&nbsp;Sooryanarayana Varambally ,&nbsp;Upender Manne","doi":"10.1016/j.tranon.2025.102466","DOIUrl":"10.1016/j.tranon.2025.102466","url":null,"abstract":"<div><h3>Purpose</h3><div>In the United States, African Americans (AA) have higher Pancreatic ductal adenocarcinoma (PDAC) incidence and mortality rates than Caucasian Americans (CA). This study aimed to identify distinct gene expression signatures and differentially regulated pathways in AA and CA PDACs.</div></div><div><h3>Methods</h3><div>Transcriptomic analyses were conducted on FFPE sections of PDACs (<em>n</em> = 40) from AA (9 PDACs/3 normal) and CA (31 PDACs/5 normal) tissues to evaluate the differential expression and signaling pathways within and between racial groups and to identify distinctive and common genes/pathways.</div></div><div><h3>Results</h3><div>We identified unique differentially expressed genes in both racial groups. Distinct set genes were modulated in AA and CA PDACs, compared to their respective normal tissues. Thirteen genes (seven upregulated and six downregulated) were differentially modulated in AA PDACs vs. CA PDACs. CIBERSORT analysis revealed distinct immune cell composition, with increased resting NK cells and activated mast cells, in AA PDACs, and higher CD4 memory T cells present in CA PDACs. Canonical subtype analyses indicated a more heterogenous subtype distribution in AA PDACs, whereas CA PDACs showed a predominance of classical subtypes. Using a publicly available database, we analyzed the top 25 upregulated genes (normal vs. tumor) for AA and CA racial groups and seven differentially upregulated genes in AA PDACs vs. CA PDACs comparison for associations with survival outcomes. Eight genes (CHST15, PARP15, NUDT16, SERPINB3, PADI1, H3C8, ZNF488, and LETM2) correlated with poor patient survival.</div></div><div><h3>Conclusion</h3><div>These findings show distinct gene expression profiles and modulated pathways in AA and CA PDACs, supporting development of race-based therapeutic targets.</div></div>","PeriodicalId":48975,"journal":{"name":"Translational Oncology","volume":"59 ","pages":"Article 102466"},"PeriodicalIF":5.0,"publicationDate":"2025-07-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144548337","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}

{"title":"Treatment of colorectal peritoneal metastases with oxaliplatin induces biomarkers predicting response to immune checkpoint blockade","authors":"Alexander Constantinides ,&nbsp;Nico Lansu ,&nbsp;Peter Mosen ,&nbsp;Paulien Rauwerdink ,&nbsp;Esther Strating ,&nbsp;Franziska Völlmy ,&nbsp;Maaike Nederend ,&nbsp;Jeanette H.W. Leusen ,&nbsp;Koen Rovers ,&nbsp;Emma Wassenaar ,&nbsp;Robin Lurvink ,&nbsp;Maarten Altelaar ,&nbsp;Simon Nienhuijs ,&nbsp;Rene Wiezer ,&nbsp;Inne H.M. Borel Rinkes ,&nbsp;Djamila Boerma ,&nbsp;Geert J.P.L. Kops ,&nbsp;Ignace de Hingh ,&nbsp;Onno Kranenburg","doi":"10.1016/j.tranon.2025.102464","DOIUrl":"10.1016/j.tranon.2025.102464","url":null,"abstract":"<div><h3>Background</h3><div>Colorectal cancer (CRC) patients with inoperable peritoneal metastases (PM) have a dismal prognosis with limited treatment options. Local treatment of CRC-PM with oxaliplatin is commonly applied, but biomarkers steering patient selection, or informing potentially effective combination therapies are lacking. A novel potentially effective treatment strategy is Pressurized IntraPeritoneal Aerosol Chemotherapy (PIPAC) in which CRC-PM are exposed to cyclic treatment with high concentrations of locally applied oxaliplatin. However, it is unclear whether and how CRC-PM respond to PIPAC.</div></div><div><h3>Methods</h3><div>Here, we generated a biobank from 20 patients receiving PIPAC with oxaliplatin for CRC-PM. The biobank contains biopsies from 3 PM per patient, repeatedly sampled prior to each treatment cycle, and ascites. Anti-tumor effects were analyzed by shallow single-cell karyotype sequencing (sc-karyoSeq). RNA-sequencing and proteomics were performed to assess changes in gene and protein expression. Immunohistochemistry was performed to assess treatment-induced changes in tissue histology. Ascites was used to assess immunoglobulin content and reactivity.</div></div><div><h3>Results</h3><div>PIPAC reduced genomic heterogeneity and aneuploidy scores among PIPAC-surviving tumor cells. Furthermore, PIPAC reduced immunosuppressive signals (hypoxia, interleukin-10, transforming growth factor β), and induced an influx of B and T lymphocytes, which organized into metastasis-associated Tertiary Lymphoid Structures (TLS). TLS are biomarkers predicting response to Immune-Checkpoint Inhibitors (ICIs). The T cells residing in PIPAC-induced TLS expressed high levels of the checkpoints PD-1, TIGIT and EBI3. PIPAC also caused the generation of plasma cells producing tumor-reactive antibodies.</div></div><div><h3>Conclusion</h3><div>PIPAC shows modest anti-tumor activity and induces immune parameters predicting response to ICIs. Patients with inoperable CRC-PM may therefore benefit from PIPAC in combination with ICIs.</div></div>","PeriodicalId":48975,"journal":{"name":"Translational Oncology","volume":"59 ","pages":"Article 102464"},"PeriodicalIF":5.0,"publicationDate":"2025-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144516947","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}

{"title":"Isolated tumor cell clusters (ITC) in lymph nodes and PD-L1 expression on tumor-associated immune cells are prognostic factors for microsatellite instable-high gastric cancers","authors":"Menghan Cui ,&nbsp;Yangli Zhou ,&nbsp;Yin Han ,&nbsp;Nannan Chen ,&nbsp;Min Zhao ,&nbsp;Yan Wang ,&nbsp;Fengxia He","doi":"10.1016/j.tranon.2025.102465","DOIUrl":"10.1016/j.tranon.2025.102465","url":null,"abstract":"<div><h3>Background</h3><div>Microsatellite instable-high (MSI-H) gastric cancer (GC) represents a distinct subgroup. However, controversy exists regarding the role of MSI in GCs, and the factors leading to internal prognostic differences among MSI-H GCs are rarely studied.</div></div><div><h3>Methods</h3><div>We identified 53 MSI-H cases from 941 consecutive GCs and conducted a detailed investigation of the clinical significance, clinicopathological correlations, and prognostic indicators of MSI-H GCs.</div></div><div><h3>Results</h3><div>Compared to MSI-low (MSI-L)/microsatellite stable (MSS) GCs, the MSI-H cohort was characterized by older age, female predominance, antral location, fewer lymph node (LN) metastases (H&amp;E), and earlier tumor stage, but was also associated with larger tumor size, poor differentiation, and a high incidence of isolated tumor cell clusters (ITC) in negative LNs. ITC was then found to be correlated with tumor volume, Lauren subtype, pT stage, LN status (H&amp;E), and lymphovascular invasion, with tumor size identified as an independent risk factor. Regarding prognosis, MSI-H GCs did not show longer survival time compared to MSI-L/MSS cases overall and in Stage Ⅲ-Ⅳ, but exhibited shorter survival time in Stage Ⅰ-Ⅱ. Moreover, in addition to age, pN stage, and distant metastasis, ITC and PD-L1 expression influenced survival in MSI-H GCs. ITC was confirmed as an independent unfavorable prognostic factor, while PD-L1 expression on interstitial immune cells independently predicted a favorable outcome.</div></div><div><h3>Conclusions</h3><div>Our results suggest that MSI-H GC represents a peculiar clinicopathological entity with frequent occurrence of ITC in negative LNs. ITC and PD-L1 are crucial prognostic indicators for MSI-H patients.</div></div>","PeriodicalId":48975,"journal":{"name":"Translational Oncology","volume":"59 ","pages":"Article 102465"},"PeriodicalIF":5.0,"publicationDate":"2025-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144516948","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}