Translational Oncology最新文献

{"title":"Germline mutation analysis and postoperative recurrence risk prediction in breast cancer patients from western China","authors":"Zhujun Deng ,&nbsp;Xia Xiao ,&nbsp;Biqin Mou,&nbsp;Jing Wang,&nbsp;Qiongxia Hu,&nbsp;Juan Jiang,&nbsp;Kang Xie,&nbsp;Wengeng Zhang,&nbsp;Weimin Li,&nbsp;Bojiang Chen","doi":"10.1016/j.tranon.2025.102477","DOIUrl":"10.1016/j.tranon.2025.102477","url":null,"abstract":"<div><h3>Background</h3><div>Much of our understanding of the germline mutation spectrum derives from hereditary breast cancer data in white populations. Additionally, the influence of genetic variants on breast cancer prognosis remains a topic of debate. Identifying patients at high risk of postoperative recurrence is crucial for guiding clinical decision-making; however, there is currently no reliable multigene risk prediction model tailored to the Chinese population.</div></div><div><h3>Methods</h3><div>A single-center retrospective study involving 1067 breast cancer patients was conducted. Survival analyses were performed using the Kaplan‒Meier method and Cox proportional hazards regression. Postoperative recurrence risk prediction models were developed utilizing the Cox regression methodology.</div></div><div><h3>Results</h3><div>In this cohort, 229 germline pathogenic/likely pathogenic (P/LP) mutations were identified in 215 patients (20.1 %). No significant differences in disease-free survival (DFS) were observed between germline P/LP mutation carriers and non-carriers. However, 10 single-nucleotide polymorphisms (SNPs) were significantly associated with DFS outcomes. By integrating the SNP status and clinical phenotype, a postoperative recurrence risk prediction model was established. The area under the curve values for 1- and 3-year DFS in the training set were 0.840 and 0.754. This model can accurately predict the DFS of patients in both the training set (hazard ratio [HR] 5.23, 95 % confidence interval [CI] 2.96–9.34; <em>p</em> &lt; 0.0001) and the validation set (HR 2.88, 95 % CI 1.41–6.06; <em>p</em> = 0.003)</div></div><div><h3>Conclusion</h3><div>In patients with early and locally advanced breast cancer, SNPs, rather than germline P/LP mutations, impact DFS. Using a genetic-clinical model, we successfully identified patients at high risk of postoperative recurrence.</div></div>","PeriodicalId":48975,"journal":{"name":"Translational Oncology","volume":"60 ","pages":"Article 102477"},"PeriodicalIF":5.0,"publicationDate":"2025-07-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144721452","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":"Aptamer-mediated delivery of therapeutic oligonucleotides in glioblastoma","authors":"Giorgia Castellani ,&nbsp;Mariachiara Buccarelli ,&nbsp;Enza Cece ,&nbsp;Martina Offi ,&nbsp;Lucia Ricci-Vitiani","doi":"10.1016/j.tranon.2025.102485","DOIUrl":"10.1016/j.tranon.2025.102485","url":null,"abstract":"<div><div>Aptamers are single-stranded oligonucleotides with great versatility, acting as therapeutic molecules with anticancer properties but also as delivery systems. A growing number of studies showed that aptamers can be properly designed to recognize a specific target, to conjugate drugs, nanoparticles or nucleic acid therapeutics (NATs) and to cross the blood brain barrier. In this review, we summarized the main advantages of aptamers as delivery system, focusing our attention on aptamer-mediated delivery of therapeutic oligonucleotides in glioblastoma. Glioblastoma represents the most common and aggressive primary malignant brain tumor in adults, with a median survival ranging from 14.6 to 20.5 months. Currently, the standard treatment of newly diagnosed tumor includes surgical resection followed by radiotherapy and chemotherapy with the alkylating agent temozolomide. However, the overall efficacy is limited and most patients relapse within a few months, calling attention on the development of alternative therapeutic strategies. Particularly, we discussed research studies on NAT delivery mediated by aptamer chimeras and aptamer-nanoparticle complexes able to impair various processes involved in glioblastoma tumorigenesis. This overview will help to highlight how aptamers, thanks to their advantages, could represent a promising tool for the development of innovative therapeutic approaches for glioblastoma treatment.</div></div>","PeriodicalId":48975,"journal":{"name":"Translational Oncology","volume":"60 ","pages":"Article 102485"},"PeriodicalIF":5.0,"publicationDate":"2025-07-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144711560","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":"MetInfilt: A prospective trial highlighting the importance of the histological growth pattern in brain metastases","authors":"Martin A. Proescholdt ,&nbsp;Tommaso Araceli ,&nbsp;Karl-Michael Schebesch ,&nbsp;Christian Doenitz ,&nbsp;Christina Wendl ,&nbsp;Katja Evert ,&nbsp;Ekaterina Noeva ,&nbsp;Julius Hoehne ,&nbsp;Markus J. Riemenschneider ,&nbsp;Daniela Hirsch ,&nbsp;Nils Ole Schmidt ,&nbsp;Daniela Sparrer ,&nbsp;Florian Lüke ,&nbsp;Daniel Heudobler ,&nbsp;Tobias Pukrop ,&nbsp;Raquel Blazquez","doi":"10.1016/j.tranon.2025.102480","DOIUrl":"10.1016/j.tranon.2025.102480","url":null,"abstract":"<div><h3>Background</h3><div>While the histological growth pattern (HGP) of liver metastases is frequently evaluated, the same attention is often absent for brain metastases despite evidence suggesting its prognostic significance. This oversight may stem from the lack of a standardized method for assessing the HGP at the macro-metastasis / brain parenchyma interface (MMPI_brain). MetInfilt is the first prospective, imaging-guided trial aimed at standardizing the collection and analysis of the HGP at the MMPI_brain.</div></div><div><h3>Methods</h3><div>We recruited fifty patients. The MMPI_brain was identified using preoperative contrast-enhanced T1-weighted MRI. Intraoperative confocal microscopy (CONVIVO) visualized the MMPI_brain, while a YELLOW 560 nm filter in the surgical microscope facilitated precise tissue sampling. Samples from the MMPI_brain and the core of the metastasis were collected for postoperative histological confirmation.</div></div><div><h3>Results</h3><div>The protocol achieved successful tissue acquisition from the MMPI_brain in 93.2 % of patients, meeting the study's primary endpoint. Preoperative MRI patterns strongly correlated with infiltrative HGPs, and CONVIVO accurately visualized the MMPI_brain intraoperatively. Exploratory analyses suggest that infiltrative HGPs might negatively impact patient prognosis and represent a potential risk of meningeal metastasis.</div></div><div><h3>Conclusions</h3><div>Our neurosurgical protocol allows the successful and precise acquisition of tissue from the MMPI_brain through presurgical imaging, intraoperative microscopy, and fluorescence-assisted sampling. The evaluation of the HGP in our limited patient cohort highlights its potential clinical significance and supports the urgent necessity to investigate it further for the benefit of patients with brain metastases.</div></div><div><h3>Clinical trial registration number</h3><div>Z-2019–1307–9.</div></div>","PeriodicalId":48975,"journal":{"name":"Translational Oncology","volume":"60 ","pages":"Article 102480"},"PeriodicalIF":5.0,"publicationDate":"2025-07-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144703021","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":"Expanded and activated marrow-infiltrating lymphocytes exhibit potent antimyeloma activity against autologous multiple myeloma cells","authors":"Seo-Yeon Ahn ,&nbsp;Manh-Cuong Vo ,&nbsp;Van-Tan Nguyen ,&nbsp;Van-Dinh-Huan Tran ,&nbsp;Tien Nguyen Duc ,&nbsp;Mihee Kim ,&nbsp;Ga-Young Song ,&nbsp;Jae-Sook Ahn ,&nbsp;Deok-Hwan Yang ,&nbsp;Hyeoung-Joon Kim ,&nbsp;Sung-Hoon Jung ,&nbsp;Je-Jung Lee","doi":"10.1016/j.tranon.2025.102475","DOIUrl":"10.1016/j.tranon.2025.102475","url":null,"abstract":"<div><div>Adoptive immunotherapy represents a promising treatment for multiple myeloma (MM), relying on the availability of sustainable tumor-specific cytotoxic T cells. This study generated potent <em>ex vivo</em> expanded and activated marrow-infiltrating lymphocytes (eMILs) from MM patients and evaluated their immunologic characteristics and cytotoxic potential. MILs were expanded using anti-CD3/CD28 beads in the presence of IL-2, IL-7, and IL-15. The expansion rate, proportions of effector cells (including CD4⁺ <em>T</em> cells, CD8⁺ <em>T</em> cells, natural killer cells, and memory T cells), and the functional capacity of eMILs were assessed over 2 weeks of culture. Co-culturing MILs with anti-CD3/CD28 beads and cytokines resulted in substantial expansion and activation of MILs during the 14-day culture period. The eMILs displayed an increased proportion of CD8⁺ <em>T</em> cells and a high prevalence of central memory T cells (Tcm; &gt; 80 %), with minimal presence of myeloid-derived suppressor cells or regulatory T cells. Compared to expanded peripheral blood lymphocytes, eMILs demonstrated potent cytotoxicity against target MM cells, particularly CD138⁺ primary MM cells from autologous patients. These findings suggest that MILs derived from the bone marrow (BM) of MM patients can be expanded and activated to exhibit enhanced antigen specificity for CD138⁺ MM cells. Furthermore, eMILs may induce sustained cytotoxic effects due to their high proportion of Tcms. In conclusion, as a unique subset of T cells shaped by the BM microenvironment, MILs show promise as a novel immunotherapeutic approach for MM.</div></div>","PeriodicalId":48975,"journal":{"name":"Translational Oncology","volume":"60 ","pages":"Article 102475"},"PeriodicalIF":5.0,"publicationDate":"2025-07-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144702463","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":"Understanding the heterogeneity of pancreatic ductal adenocarcinoma","authors":"Juan Iovanna ,&nbsp;Nicolas Fraunhoffer ,&nbsp;Raul Urrutia ,&nbsp;Nelson Dusetti","doi":"10.1016/j.tranon.2025.102479","DOIUrl":"10.1016/j.tranon.2025.102479","url":null,"abstract":"<div><div>Pancreatic ductal adenocarcinoma (PDAC) is a highly aggressive, treatment-resistant cancer characterized by extensive inter- and intra-tumoral heterogeneity. Although over 95 % of cases harbor KRAS mutations and commonly altered tumor suppressors like TP53, SMAD4, and CDKN2A, these genetic changes alone do not fully explain PDAC variability. We propose a paradigm shift: PDAC heterogeneity is not solely genetic but also shaped by epigenetic regulation and the tumor microenvironment. Traditional transcriptomic classifications define PDAC into fixed subtypes, primarily classical and basal-like, but we argue these are not static categories. Instead, PDAC phenotypes exist along a dynamic continuum influenced by stromal interactions and epigenetic cues. This model challenges the binary classification view. We show that transitions from classical to basal-like states are gradual and reversible, driven by tumor-stroma crosstalk and chromatin remodeling. Such plasticity underpins tumor adaptation, resistance, and progression. Embracing this dynamic framework offers novel therapeutic opportunities.</div></div>","PeriodicalId":48975,"journal":{"name":"Translational Oncology","volume":"60 ","pages":"Article 102479"},"PeriodicalIF":5.0,"publicationDate":"2025-07-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144678941","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":"AGEs-RAGE manipulates tumor intrinsic pERK/Sp1/IL6 pathway and reprograms macrophage to promote intrahepatic cholangiocarcinoma progression","authors":"Juan Zhang ,&nbsp;Biyang Jing ,&nbsp;Xiaojian Ni ,&nbsp;Youpei Lin ,&nbsp;Jiaomeng Pan ,&nbsp;MaoPei Chen ,&nbsp;Boheng Zhang ,&nbsp;Lan Zhang ,&nbsp;Ningling Ge ,&nbsp;Ruyuan Deng ,&nbsp;Xiao Wang ,&nbsp;Guohe Song","doi":"10.1016/j.tranon.2025.102446","DOIUrl":"10.1016/j.tranon.2025.102446","url":null,"abstract":"<div><div>Tumors often exhibit oxygen deprivation and enhanced glucose uptake, leading to glycolysis. Advanced glycation end products (AGEs) protein modifications induced by hyperglycemia—activate signaling pathways that promote cancer progression upon binding to its receptor (RAGE). In this study, AGEs-treatment enhanced the growth, invasion and migration of intrahepatic cholangiocarcinoma cells (ICC), while increasing IL-6 expression and secretion. Meanwhile, AGEs stimulated the expression of RAGE, specificity protein 1 (Sp1), and the phosphorylation of extracellular signal-regulated kinase (ERK) in a dose-dependent manner. However, these effects were attenuated by RAGE antibody blockade, RAGE knockdown, the ERK inhibitor U0126, or Sp1-specific siRNA. Furthermore, the supernatant of AGEs-treated RBE cells induced M2 polarization of THP-1 macrophages. Thus, AGEs promote ICC progression partly through the pERK/Sp1/IL-6 pathway and M2 macrophage polarization. These findings highlight underscore the role of the AGEs-RAGE axis in driving ICC progression via pERK/Sp1/IL-6 signaling.</div></div>","PeriodicalId":48975,"journal":{"name":"Translational Oncology","volume":"60 ","pages":"Article 102446"},"PeriodicalIF":5.0,"publicationDate":"2025-07-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144678942","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":"Global, regional, and national estimates of burden and risk factors of female cancers in child-bearing age: A systematic analysis for Global Burden of Disease Study and Bayesian projection to 2030","authors":"Guang Chen ,&nbsp;Shichen Zhou ,&nbsp;Qiaoxin Shi ,&nbsp;Yunqing Xun ,&nbsp;Tung-Leong Fong ,&nbsp;Ruogu Xiong ,&nbsp;Ya Xuan Sun ,&nbsp;Junjie Lu ,&nbsp;Yige Li ,&nbsp;Zheng Li ,&nbsp;Guanghui Zhu ,&nbsp;Ying Wu ,&nbsp;Yang Zhou ,&nbsp;Yibin Feng ,&nbsp;Karen K.L. CHAN","doi":"10.1016/j.tranon.2025.102473","DOIUrl":"10.1016/j.tranon.2025.102473","url":null,"abstract":"<div><h3>Background</h3><div>The prevention, management, and treatment of female cancers among women of childbearing age (WCBA) are crucial strategies for achieving the objectives outlined in the World Health Organization (WHO) Global Breast Cancer Initiative and Cervical Cancer Elimination Initiative. This review aims to provide comprehensive global, regional, and national estimates of the burden of female cancers in women of childbearing age, as well as their attributable risk factors, from 1990 to 2021.</div></div><div><h3>Methods</h3><div>According to the Global Burden of Diseases, Injuries, and Risk Factors Study (GBD) 2021 methodology, we estimated the incidence, disability-adjusted life-years (DALYs), and mortality of breast, cervical, ovarian, and uterine cancer among women of childbearing age. Temporal trends were assessed using the age-adjusted percentage change (AAPC). Risk factors were estimated using the population attributable fraction, stratified by socio-demographic index (SDI). Projections to 2030 were generated using a Bayesian model.</div></div><div><h3>Results</h3><div>In 2021, the global incidence of breast, uterine, cervical, and ovarian cancer among WCBA was 561,438 (95 % Uncertainty Interval [UI]: 523,147–602,978), 58,860 (95 % UI: 50,765–65,452), 307,428 (95 % UI: 280,667–335,692), and 85,749 (95 % UI: 75,169–95,090), respectively, corresponding to age-standardized rates per 100,000 population of 28.1 (95 % Confidence Interval [CI]: 28.0–28.1), 2.9 (95 % CI: 2.9–3.0), 15.4 (95 % CI: 15.4–15.5), and 4.3 (95 % CI: 4.3–4.4). Breast cancer accounted for the highest number of DALYs at 6659,460 (95 % UI: 6192,226–7145,549), followed by cervical cancer at 4184,314 (95 % UI: 3779,640–4629,604). Diets high in red meat, smoking, and alcohol consumption contributed to 11.2 %, 2.5 %, and 2.6 % of breast cancer deaths, respectively, while unprotected sex accounted for majority of cervical cancer deaths. Obesity was responsible for 30.2 % of both ovarian and uterine cancer deaths. Bayesian projection models indicated that by 2030, the global age-standardized incidence rates of breast and ovarian cancers among WCBA will reach 31.5 and 4.7 per 100,000 population, respectively.</div></div><div><h3>Conclusion</h3><div>Globally, the number of breast, uterine, and ovarian cancer cases among WCBA has increased over the past decade, accompanied by a steady rise in age-standardized incidence rates. In contrast, while the absolute number of cervical cancer cases has risen, its age-standardized incidence rate has declined. Mortality rates for both breast and cervical cancers have generally decreased worldwide; however, in countries within the lower SDI quintile, mortality rates for these cancers continue to rise. Therefore, priority should be given to initiatives such as smoking cessation programs, alcohol reduction strategies, HPV vaccination campaigns, and safe sex education, particularly in lower SDI countries.</div></div>","PeriodicalId":48975,"journal":{"name":"Translational Oncology","volume":"60 ","pages":"Article 102473"},"PeriodicalIF":5.0,"publicationDate":"2025-07-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144665967","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":"Epigenetic insights: unveiling the impact of hypomethylated CACNA2D3 and FLNA genes in breast cancer progression","authors":"Samar Sindi ,&nbsp;Safiah Alhazmi ,&nbsp;Mansour Alsaleem ,&nbsp;Sabah Hassan ,&nbsp;Magdah Ganash ,&nbsp;Aisha Alrofidi ,&nbsp;Khloud Algothmi ,&nbsp;Shadi Alkhayyat ,&nbsp;Ayman Linjawi ,&nbsp;Aisha Elaimi ,&nbsp;Saif Alharthy ,&nbsp;Heba Alkhatabi","doi":"10.1016/j.tranon.2025.102469","DOIUrl":"10.1016/j.tranon.2025.102469","url":null,"abstract":"<div><div>Breast Cancer (BC) remains a significant cause of cancer-related mortality in women, impacted by complex genetic and epigenetic alterations in its progression. Among these processes is DNA hypomethylation, which promotes cancer growth. This study aimed to detect the expression level and methylation status of <em>CACNA2D3</em> and <em>FLNA</em> genes in breast cancer patients and then assess the relationship between the mRNA expression and clinicopathological characteristics, as well as the survival rate of these genes. Two advanced techniques, whole genome bisulfite sequencing (WGBS) and differentially expressed WGBS (DEGs), were used to assess the expression and methylation levels. To analyze the pathways that were altered in breast cancer, the WebGestalt over-representation analysis tool (ORA) was used to perform gene ontology (GO) for the highly expressed hypomethylated genes in BC samples. Moreover, the Molecular Taxonomy of Breast Cancer International Consortium (METABRIC) cohort, The Cancer Genome Atlas (TCGA), and Kaplan-Meier Plotter datasets were used to examine the predictive significance of the <em>CACNA2D3</em> and <em>FLNA</em> genes. Then, 5-aza-2′-deoxycytidine (5-AZA) treatment was applied to examine the relationship between DNA methylation and gene expression in MCF7 and MCF10A cells. The results of these advanced techniques indicated that <em>CACNA2D3</em> and <em>FLNA</em> exhibited a significant difference in gene expression and methylation levels between breast cancer patients and controls. The data analysis from several public domains of BC datasets showed that the MAPK pathway was the most significant pathway in BC (p-value 0.035) with four overlapping aberrant hypomethylated genes (<em>ANGPT1, CACNA2D3, FLNA</em>, and <em>IKBKG</em>). Moreover, the <em>CACNA2D3</em> gene was associated with tumor size, histological grade, estrogen receptor (ER), and progesterone receptor (PR) status. Furthermore, <em>CACNA2D3</em> gene expression was increased after 5-AZA treatment in two cell lines, while <em>FLNA</em> gene showed fluctuations in its expression, suggesting that additional factors regulate <em>FLNA</em> expression, which could be related to tumor size, histology, ER, and PR. In conclusion, DNA methylation could be a regulatory factor for <em>CACNA2D3</em> and its high expression was linked to clinicopathological characteristics of breast cancer patients, especially with a good prognosis.</div></div>","PeriodicalId":48975,"journal":{"name":"Translational Oncology","volume":"60 ","pages":"Article 102469"},"PeriodicalIF":5.0,"publicationDate":"2025-07-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144656529","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":"Immune-checkpoint inhibition for tumor prevention in a preclinical Lynch syndrome model","authors":"Annabell Wolff ,&nbsp;Johanna Maennicke ,&nbsp;Maja Huehns ,&nbsp;Paula Krone ,&nbsp;Sonja Oehmcke-Hecht ,&nbsp;Caterina Redwanz ,&nbsp;Wendy Bergmann-Ewert ,&nbsp;Christian Junghanss ,&nbsp;Claudia Maletzki","doi":"10.1016/j.tranon.2025.102472","DOIUrl":"10.1016/j.tranon.2025.102472","url":null,"abstract":"<div><h3>Background</h3><div>FDA-approved immune checkpoint inhibitors (ICIs) are the state-of-the-art treatment for mismatch-repair deficient tumors (dMMR). Their immunomodulatory effects in a preventive setting, are poorly studied. In this study, we used two ICIs against PD-L1 or LAG-3 in a preclinical mouse model of dMMR-driven carcinogenesis.</div></div><div><h3>Methods</h3><div>Msh2^{loxP/loxP; TgTg(Vil1-cre} mice without clinical signs of tumor development (i.e. age &lt;12 weeks) received repeated applications (<em>n</em> = 8, 28-day interval) of anti-PD-L1, anti-LAG-3 (2.5 mg/kg bw, i.p.) or isotype (anti-IgG1, 2.5 mg/kg bw, i.p.). Blood phenotyping, tumor microenvironment, and hematopoiesis, and presence of procoagulant extracellular vesicles (EV) were studied.</div></div><div><h3>Results</h3><div>Prophylactic ICI application significantly prolonged overall survival (OS) of Msh2^{loxP/loxP; TgTg(Vil1-cre} mice (OS: anti-PD-L1: 54.4 wks and anti-LAG-3: 58.4 wks vs. ctrl 35.8 wks). Circulating exhausted and regulatory T cells were significantly lower in the ICI groups. Splenic exhaustion markers showed correlating results. Outgrowing tumors showed an inflammatory response-related gene signature. Accompanying immunofluorescence confirmed data and identified reduced numbers of tumor-infiltrating regulatory granulocytes in late-onset tumors. Alterations in bone marrow hematopoiesis accompanied this massive immune modulation, indicating successful prevention of myeloid-shifted hematopoiesis. Plasma coagulation of EVs was not significantly altered in the ICI groups.</div></div><div><h3>Conclusion</h3><div>Preventive ICI prolongs overall survival of cancer-prone mice. The sustained immune modulation and normal bone marrow hematopoiesis may pre-sensitize late-onset dMMR tumors to a second round of immunotherapy. Hence, we highlight the importance of preventive strategies for germline MMR mutation carriers and recommend improved screening of patients eligible for prophylactic ICIs to improve long-term outcomes.</div></div>","PeriodicalId":48975,"journal":{"name":"Translational Oncology","volume":"60 ","pages":"Article 102472"},"PeriodicalIF":5.0,"publicationDate":"2025-07-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144656530","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":"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}