Pub Date : 2025-08-22DOI: 10.1016/j.neo.2025.101220
L Recalde-Percaz , I de la Guia-Lopez , P Linzoain-Agos , A Noguera-Castells , M Rodrigo-Faus , P Jauregui , A Lopez-Plana , P Fernández-Nogueira , M Iniesta-González , M Cueto-Remacha , S Manzano , R Alonso , N Moragas , C Baquero , N Palao , E Dalla , FX Avilés-Jurado , I Vilaseca , X León-Vintró , M Camacho , P Bragado
Metastasis is the main cause of death from solid tumors. Therefore, identifying the mechanisms that govern metastatic growth poses a major biomedical challenge. Tumor microenvironment signals regulate the fate and survival of disseminated tumor cells (DTCs) in secondary organs. However, very little is known about the role of nervous system mediators in this process. We have previously reported that neuropilin-2 (NRP2) expression in breast cancer correlates with poor prognosis. Here, we show that NRP2 positively regulates the proliferation, invasion, and survival of breast and head and neck cancer cells in vitro. NRP2 deletion in tumor cells inhibits tumor growth in vivo and decreases the number and size of lung metastases by promoting lung DTCs quiescence. NRP2 deletion upregulates dormancy and cell cycle regulators expression and promotes DTCs reprograming into quiescence. Moreover, lung fibroblasts and macrophages induce NRP2 upregulation in DTCs through the secretion of TGFβ1. NRP2 facilitates lung DTC interaction with the extracellular matrix and promotes lung DTCs activation and metastasis. Therefore, we conclude that the TGFβ1-NRP2 axis is a new key dormancy-awakening inducer that promotes DTCs proliferation and lung metastasis development.
{"title":"Neuropilin-2 upregulation by stromal TGFβ1 induces lung disseminated tumor cells dormancy escape and promotes metastasis outgrowth","authors":"L Recalde-Percaz , I de la Guia-Lopez , P Linzoain-Agos , A Noguera-Castells , M Rodrigo-Faus , P Jauregui , A Lopez-Plana , P Fernández-Nogueira , M Iniesta-González , M Cueto-Remacha , S Manzano , R Alonso , N Moragas , C Baquero , N Palao , E Dalla , FX Avilés-Jurado , I Vilaseca , X León-Vintró , M Camacho , P Bragado","doi":"10.1016/j.neo.2025.101220","DOIUrl":"10.1016/j.neo.2025.101220","url":null,"abstract":"<div><div>Metastasis is the main cause of death from solid tumors. Therefore, identifying the mechanisms that govern metastatic growth poses a major biomedical challenge. Tumor microenvironment signals regulate the fate and survival of disseminated tumor cells (DTCs) in secondary organs. However, very little is known about the role of nervous system mediators in this process. We have previously reported that neuropilin-2 (NRP2) expression in breast cancer correlates with poor prognosis. Here, we show that NRP2 positively regulates the proliferation, invasion, and survival of breast and head and neck cancer cells <em>in vitro</em>. NRP2 deletion in tumor cells inhibits tumor growth <em>in vivo</em> and decreases the number and size of lung metastases by promoting lung DTCs quiescence. NRP2 deletion upregulates dormancy and cell cycle regulators expression and promotes DTCs reprograming into quiescence. Moreover, lung fibroblasts and macrophages induce NRP2 upregulation in DTCs through the secretion of TGFβ1. NRP2 facilitates lung DTC interaction with the extracellular matrix and promotes lung DTCs activation and metastasis. Therefore, we conclude that the TGFβ1-NRP2 axis is a new key dormancy-awakening inducer that promotes DTCs proliferation and lung metastasis development.</div></div>","PeriodicalId":18917,"journal":{"name":"Neoplasia","volume":"68 ","pages":"Article 101220"},"PeriodicalIF":7.7,"publicationDate":"2025-08-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144886248","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}
Pub Date : 2025-08-21DOI: 10.1016/j.neo.2025.101221
Zofia M. Komar , Mieke Bavelaar , Ellen Kageler , Nicole S. Verkaik , Mandy M. van Rosmalen , Carolien H.M. van Deurzen , Michael A. den Bakker , Roland Kanaar , Adriaan B Houtsmuller , Thierry P.P. van den Bosch , Agnes Jager , Dik C. van Gent
Personalized medicine for breast cancer (BrC) requires predictive biomarkers to select the optimal therapeutic option for each individual patient. Personalization of chemotherapy or immunotherapy responses is particularly challenging, as molecular markers do not appear to be sufficiently predictive for therapy response. Functional assays for therapy selection may be the solution for this dilemma. An interesting approach is ex vivo cultures of precision cut tumor slices, such as the MOtion-based Tissue EX vivo (MOTEX) method that we described previously. This culture method has the advantage that it carries all cell types in the tumor, including various immune cell populations. We here show, that macrophages, B-cells and T-cell populations are maintained in the MOTEX culture for several days without apparent loss of viability. Even treatment with the microtubule poison paclitaxel did not reduce immune cell abundance or viability significantly. Anthracycline-based chemotherapy, however, did affect immune cell composition, as expected based on its cytotoxic properties. Therefore, we conclude that MOTEX culture of BrC tissue slices can be used to investigate effect of treatments that involve the immune system. This opens perspectives to develop predictive assays for immune checkpoint inhibitor treatment and other therapeutic interventions that require immune components in the assay system.
{"title":"Motion based ex vivo (MOTEX) culture of breast tumor slices sustains microenvironment composition","authors":"Zofia M. Komar , Mieke Bavelaar , Ellen Kageler , Nicole S. Verkaik , Mandy M. van Rosmalen , Carolien H.M. van Deurzen , Michael A. den Bakker , Roland Kanaar , Adriaan B Houtsmuller , Thierry P.P. van den Bosch , Agnes Jager , Dik C. van Gent","doi":"10.1016/j.neo.2025.101221","DOIUrl":"10.1016/j.neo.2025.101221","url":null,"abstract":"<div><div>Personalized medicine for breast cancer (BrC) requires predictive biomarkers to select the optimal therapeutic option for each individual patient. Personalization of chemotherapy or immunotherapy responses is particularly challenging, as molecular markers do not appear to be sufficiently predictive for therapy response. Functional assays for therapy selection may be the solution for this dilemma. An interesting approach is <em>ex vivo</em> cultures of precision cut tumor slices, such as the MOtion-based Tissue EX vivo (MOTEX) method that we described previously. This culture method has the advantage that it carries all cell types in the tumor, including various immune cell populations. We here show, that macrophages, B-cells and T-cell populations are maintained in the MOTEX culture for several days without apparent loss of viability. Even treatment with the microtubule poison paclitaxel did not reduce immune cell abundance or viability significantly. Anthracycline-based chemotherapy, however, did affect immune cell composition, as expected based on its cytotoxic properties. Therefore, we conclude that MOTEX culture of BrC tissue slices can be used to investigate effect of treatments that involve the immune system. This opens perspectives to develop predictive assays for immune checkpoint inhibitor treatment and other therapeutic interventions that require immune components in the assay system.</div></div>","PeriodicalId":18917,"journal":{"name":"Neoplasia","volume":"68 ","pages":"Article 101221"},"PeriodicalIF":7.7,"publicationDate":"2025-08-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144879604","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}
Pub Date : 2025-08-20DOI: 10.1016/j.neo.2025.101219
Peng Li , Guangshi Liu , Wenbin Zhang , Tao Li , Xinhui Yang
Background
Tumor angiogenesis is essential for colorectal cancer (CRC) progression, providing oxygen and nutrients to sustain tumor growth and metastasis. Protein kinase C iota (Prkci) is an atypical protein kinase known for its oncogenic roles in various cancers; however, its function in CRC angiogenesis remains largely unexplored. This study investigates the role of Prkci in regulating tumor angiogenesis through the Jak2/Stat3 signaling pathway.
Methods
Prkci expression levels in CRC tissues and their correlation with micro-vessel density and patient prognosis were analyzed. Functional experiments, including endothelial cell proliferation, migration, and tube formation assays, were performed in vitro to assess the angiogenic effects of Prkci. In vivo, a CRC xenograft mouse model with Prkci knockout was used to evaluate tumor growth and angiogenesis. Mechanistic studies explored how Prkci activates Jak2 by phosphorylating it at the S633 site, leading to downstream Stat3 activation and Vegfa expression.
Results
Prkci was upregulated in CRC tissues and correlated with increased micro-vessel density and poor patient prognosis. In vitro, Prkci overexpression enhanced endothelial cell proliferation, migration, and tube formation, while Prkci knockout inhibited these processes. Mechanistically, Prkci phosphorylated Jak2 at S633, leading to enhanced Stat3 activation and increased Vegfa expression, which promoted angiogenesis. In vivo, Prkci knockout in CRC cells significantly reduced tumor growth, angiogenesis, and prolonged survival in a mouse model.
Conclusions
These findings identify Prkci as a key regulator of angiogenesis in CRC through Jak2/Stat3 signaling activation. Targeting Prkci could provide a novel therapeutic approach to inhibit tumor angiogenesis and limit CRC progression.
{"title":"Prkci activates Jak2/Stat3 signaling to promote tumor angiogenesis","authors":"Peng Li , Guangshi Liu , Wenbin Zhang , Tao Li , Xinhui Yang","doi":"10.1016/j.neo.2025.101219","DOIUrl":"10.1016/j.neo.2025.101219","url":null,"abstract":"<div><h3>Background</h3><div>Tumor angiogenesis is essential for colorectal cancer (CRC) progression, providing oxygen and nutrients to sustain tumor growth and metastasis. Protein kinase C iota (Prkci) is an atypical protein kinase known for its oncogenic roles in various cancers; however, its function in CRC angiogenesis remains largely unexplored. This study investigates the role of Prkci in regulating tumor angiogenesis through the Jak2/Stat3 signaling pathway.</div></div><div><h3>Methods</h3><div>Prkci expression levels in CRC tissues and their correlation with micro-vessel density and patient prognosis were analyzed. Functional experiments, including endothelial cell proliferation, migration, and tube formation assays, were performed in vitro to assess the angiogenic effects of Prkci. In vivo, a CRC xenograft mouse model with Prkci knockout was used to evaluate tumor growth and angiogenesis. Mechanistic studies explored how Prkci activates Jak2 by phosphorylating it at the S633 site, leading to downstream Stat3 activation and Vegfa expression.</div></div><div><h3>Results</h3><div>Prkci was upregulated in CRC tissues and correlated with increased micro-vessel density and poor patient prognosis. In vitro, Prkci overexpression enhanced endothelial cell proliferation, migration, and tube formation, while Prkci knockout inhibited these processes. Mechanistically, Prkci phosphorylated Jak2 at S633, leading to enhanced Stat3 activation and increased Vegfa expression, which promoted angiogenesis. In vivo, Prkci knockout in CRC cells significantly reduced tumor growth, angiogenesis, and prolonged survival in a mouse model.</div></div><div><h3>Conclusions</h3><div>These findings identify Prkci as a key regulator of angiogenesis in CRC through Jak2/Stat3 signaling activation. Targeting Prkci could provide a novel therapeutic approach to inhibit tumor angiogenesis and limit CRC progression.</div></div>","PeriodicalId":18917,"journal":{"name":"Neoplasia","volume":"68 ","pages":"Article 101219"},"PeriodicalIF":7.7,"publicationDate":"2025-08-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144879603","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}
Pub Date : 2025-08-06DOI: 10.1016/j.neo.2025.101217
Yuxia Fu , Guoqing Zhang , Yue Liu , Lei Xu , Yuanyuan Hu , Liyan Xue , Huiqin Guo , Yan Fu , Yigang Cen , Xiao Li , Wei Jiang , Xiying Yu
The use of carcinogen-induced multistage carcinogenesis animal models of esophageal squamous cell carcinoma (CIMCM of ESCC) is limited by prolonged timelines, high toxicity, and excessive mutational burden. In this study, we report the establishment of an effective mouse CIMCM of ESCC by using 4-nitroquinoline-1-oxide (4NQO) as a carcinogen and sorafenib (SOR) as a tumor promoter. We show that SOR specifically activates the Raf-MEK-ERK signaling pathway in normal esophageal stratified squamous epithelium cells, thereby promoting tumor progression. This CIMCM of ESCC accurately recapitulates the multistage process of ESCC carcinogenesis from precancerous lesions to invasive carcinoma, with shortened time and high efficiency. Pathological, molecular, cellular and multiomic analyses show that the CIMCM of ESCC significantly reduces the tumor mutation burden to levels detected in human ESCC samples, while preserving key genetic driver mutations and abnormal transcriptomic/protein expression profiles. Notably, the CIMCM of ESCC demonstrates that the tissue microenvironment plays an important role in ESCC carcinogenesis, as the application of mechanical injury to the esophageal SSE of the CIMCM results in the inflammatory-related response, site-specific tumor formation and high tumor incidence. Since the CIMCM of ESCC provides valuable samples from different stages of tumor initiation and progression, the pathological whole slide images of the CIMCM of ESCC are applied to the computational pathology, which enables the detection, segmentation and annotation of the ESCC initiation and progression with pathologist-level accuracy. Taken together, this mouse CIMCM of ESCC provides a versatile platform for ESCC early diagnosis, basic and preclinical research and therapeutic strategy.
食管鳞状细胞癌（CIMCM of ESCC）的多阶段癌变动物模型的使用受到时间长、毒性高和突变负担过重的限制。在这项研究中，我们报道了以4-硝基喹啉-1-氧化物（4NQO）为致癌物，索拉非尼（SOR）为肿瘤促进剂，建立了有效的ESCC小鼠CIMCM。我们发现SOR特异性激活正常食管分层鳞状上皮细胞中的Raf-MEK-ERK信号通路，从而促进肿瘤进展。该方法准确概括了ESCC从癌前病变到侵袭性癌的多阶段癌变过程，时间短、效率高。病理、分子、细胞和多组学分析表明，ESCC的CIMCM显著降低了肿瘤突变负担，同时保留了关键的遗传驱动突变和异常的转录组/蛋白表达谱。值得注意的是，ESCC的CIMCM表明组织微环境在ESCC的癌变中起着重要的作用，因为机械损伤CIMCM的食管SSE导致炎症相关反应，部位特异性肿瘤形成和高肿瘤发生率。由于ESCC的CIMCM提供了肿瘤起始和进展不同阶段的宝贵样本，因此将ESCC的病理全切片图像应用于计算病理学，使ESCC起始和进展的检测、分割和注释具有病理学水平的准确性。综上所述，该小鼠ESCC的CIMCM为ESCC的早期诊断、基础和临床前研究以及治疗策略提供了一个多功能平台。
{"title":"An effective multistage mouse model of esophageal carcinogenesis for preclinical and computational pathology applications","authors":"Yuxia Fu , Guoqing Zhang , Yue Liu , Lei Xu , Yuanyuan Hu , Liyan Xue , Huiqin Guo , Yan Fu , Yigang Cen , Xiao Li , Wei Jiang , Xiying Yu","doi":"10.1016/j.neo.2025.101217","DOIUrl":"10.1016/j.neo.2025.101217","url":null,"abstract":"<div><div>The use of <em>c</em>arcinogen-<em>i</em>nduced <em>m</em>ultistage <em>c</em>arcinogenesis animal <em>m</em>odels of esophageal squamous cell carcinoma (CIMCM of ESCC) is limited by prolonged timelines, high toxicity, and excessive mutational burden. In this study, we report the establishment of an effective mouse CIMCM of ESCC by using 4-nitroquinoline-1-oxide (4NQO) as a carcinogen and sorafenib (SOR) as a tumor promoter. We show that SOR specifically activates the Raf-MEK-ERK signaling pathway in normal esophageal stratified squamous epithelium cells, thereby promoting tumor progression. This CIMCM of ESCC accurately recapitulates the multistage process of ESCC carcinogenesis from precancerous lesions to invasive carcinoma, with shortened time and high efficiency. Pathological, molecular, cellular and multiomic analyses show that the CIMCM of ESCC significantly reduces the tumor mutation burden to levels detected in human ESCC samples, while preserving key genetic driver mutations and abnormal transcriptomic/protein expression profiles. Notably, the CIMCM of ESCC demonstrates that the tissue microenvironment plays an important role in ESCC carcinogenesis, as the application of mechanical injury to the esophageal SSE of the CIMCM results in the inflammatory-related response, site-specific tumor formation and high tumor incidence. Since the CIMCM of ESCC provides valuable samples from different stages of tumor initiation and progression, the pathological whole slide images of the CIMCM of ESCC are applied to the computational pathology, which enables the detection, segmentation and annotation of the ESCC initiation and progression with pathologist-level accuracy. Taken together, this mouse CIMCM of ESCC provides a versatile platform for ESCC early diagnosis, basic and preclinical research and therapeutic strategy.</div></div>","PeriodicalId":18917,"journal":{"name":"Neoplasia","volume":"68 ","pages":"Article 101217"},"PeriodicalIF":7.7,"publicationDate":"2025-08-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144780796","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}
Pub Date : 2025-08-06DOI: 10.1016/j.neo.2025.101216
Lu Zhang , Di Jin , Jingyu Zang , Lei Qian , Tianxiang Zhang , Yuchen Wu , Yu Ding , Feng Xie , Haoran Tang , Jun Xia , Dengfeng Cao , Ruiyun Zhang , Guanglei Zhuang , Haige Chen
Purpose
Although trimodal therapy is currently the standard organ-sparing approach for muscle-invasive bladder cancer (MIBC), its clinical benefit is limited, and noninvasive biomarkers to guide dynamic decision-making are lacking. Here, we present a proof-of-concept study evaluating disitamab vedotin (RC48, a HER2-targeted antibody-drug conjugate) combined with toripalimab (JS001, anti-PD-1) and radiotherapy for bladder preservation in localized HER2-positive MIBC.
Patients and Methods
In the first-stage of an open-label phase II clinical trial (ClinicalTrials.gov identifier: NCT05979740), six patients were enrolled and received disitamab vedotin, toripalimab, and radiotherapy. Adverse events were documented according to the National Cancer Institute Common Terminology Criteria for Adverse Events (CTCAE v5.0). Tumor response was evaluated every 12 weeks by radiographic imaging, cystoscopy with biopsies, and urine cytology. In parallel, we performed longitudinal liquid biopsy analyses of circulating tumor DNA (ctDNA) and urinary tumor DNA (utDNA) using PredicineCARE assay.
Results
The combination was overall tolerable, with no grade 4 treatment-related adverse events or deaths. Five patients (83.3 %) achieved a complete response and remained recurrence-free. Notably, utDNA testing showed high accuracy in monitoring therapeutic effectiveness and enabled early detection of tumor relapse, whereas ctDNA was largely undetectable across blood samples.
Conclusions
These findings establish the feasibility, efficacy, and potential biomarker utility of a novel bladder-preserving regimen, setting the stage for a paradigm shift in MIBC management.
{"title":"Disitamab vedotin combined with toripalimab and radiotherapy for multimodal organ-sparing treatment of muscle invasive bladder cancer: a proof-of-concept study","authors":"Lu Zhang , Di Jin , Jingyu Zang , Lei Qian , Tianxiang Zhang , Yuchen Wu , Yu Ding , Feng Xie , Haoran Tang , Jun Xia , Dengfeng Cao , Ruiyun Zhang , Guanglei Zhuang , Haige Chen","doi":"10.1016/j.neo.2025.101216","DOIUrl":"10.1016/j.neo.2025.101216","url":null,"abstract":"<div><h3>Purpose</h3><div>Although trimodal therapy is currently the standard organ-sparing approach for muscle-invasive bladder cancer (MIBC), its clinical benefit is limited, and noninvasive biomarkers to guide dynamic decision-making are lacking. Here, we present a proof-of-concept study evaluating disitamab vedotin (RC48, a HER2-targeted antibody-drug conjugate) combined with toripalimab (JS001, anti-PD-1) and radiotherapy for bladder preservation in localized HER2-positive MIBC.</div></div><div><h3>Patients and Methods</h3><div>In the first-stage of an open-label phase II clinical trial (ClinicalTrials.gov identifier: NCT05979740), six patients were enrolled and received disitamab vedotin, toripalimab, and radiotherapy. Adverse events were documented according to the National Cancer Institute Common Terminology Criteria for Adverse Events (CTCAE v5.0). Tumor response was evaluated every 12 weeks by radiographic imaging, cystoscopy with biopsies, and urine cytology. In parallel, we performed longitudinal liquid biopsy analyses of circulating tumor DNA (ctDNA) and urinary tumor DNA (utDNA) using PredicineCARE assay.</div></div><div><h3>Results</h3><div>The combination was overall tolerable, with no grade 4 treatment-related adverse events or deaths. Five patients (83.3 %) achieved a complete response and remained recurrence-free. Notably, utDNA testing showed high accuracy in monitoring therapeutic effectiveness and enabled early detection of tumor relapse, whereas ctDNA was largely undetectable across blood samples.</div></div><div><h3>Conclusions</h3><div>These findings establish the feasibility, efficacy, and potential biomarker utility of a novel bladder-preserving regimen, setting the stage for a paradigm shift in MIBC management.</div></div>","PeriodicalId":18917,"journal":{"name":"Neoplasia","volume":"68 ","pages":"Article 101216"},"PeriodicalIF":7.7,"publicationDate":"2025-08-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144780795","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}
Pub Date : 2025-08-05DOI: 10.1016/j.neo.2025.101214
Tobias Feilen , Manuel Rogg , Grigor Andreev , Niko Pinter , Maximilian Wess , Anna L. Kössinger , Nastasja Diel , Elke Neumann-Haefelin , Athina Ganner , Markus Grabbert , Christoph Schell , Oliver Schilling
Von Hippel-Lindau (VHL) disease describes a hereditary tumor predisposition syndrome, caused by germline mutations in the VHL tumor suppressor gene, resulting in the functional loss of the VHL protein (pVHL). pVHL loss translates into a pseudo-hypoxic state that drives clear cell renal cell carcinoma (ccRCC) development. ccRCC tumors frequently form a pseudocapsule (PC) at the tumor boundary. This study describes the first comprehensive proteomic analysis of the PC in ccRCC patients with hereditary VHL inactivation, revealing a distinctive matrisomal signature. We conducted a deep, mass spectrometry-based proteomic analysis of 130 formalin-fixed paraffin-embedded (FFPE) ccRCC samples, comprising 54 tumor, 45 PC, and 31 non-malignant adjacent tissue (NAT) specimens from 34 patients. The PC exhibited unique matrisomal features, with pronounced enrichment of structural extracellular matrix (ECM) components, ECM processing enzymes, and secreted signaling proteins such as TGFβ2. Its proteome composition, including proteins involved in immune response, varied with tumor size and semi-tryptic peptide analysis indicated selective ECM processing in the PC and elevated levels of proteolysis within the tumor. Further, tumor proteomes reflected canonical VHL-driven metabolic reprogramming, including upregulated glycolysis and hypoxia markers, suppressed aerobic metabolism, and dysregulated fatty acid metabolism. Enriched immunoproteasome, MHC-I, and inflammasome proteins indicated an active immune response. Pro-angiogenic factors enriched in the tumor partially extended into the PC. Comparison of primary vs metachronous ccRCC cases uncovered proteomic tumor plasticity in VHL disease. Together, our study delineates the PC as an active, signaling-rich compartment at the ccRCC boundary with potential implications for tumor progression and clinical relevance beyond a mere structural scaffold.
Von Hippel-Lindau （VHL）病描述了一种遗传性肿瘤易感性综合征，由VHL肿瘤抑制基因的种系突变引起，导致VHL蛋白（pVHL）的功能丧失。pVHL缺失转化为假性缺氧状态，驱动透明细胞肾细胞癌（ccRCC）的发展。ccRCC肿瘤常在肿瘤边界形成假包膜（PC）。这项研究首次对遗传性VHL失活的ccRCC患者的PC进行了全面的蛋白质组学分析，揭示了一个独特的基质特征。我们对来自34例患者的130例福尔马林固定石蜡包埋（FFPE） ccRCC样本进行了深入的、基于质谱的蛋白质组学分析，其中包括54例肿瘤、45例PC和31例非恶性邻近组织（NAT）样本。PC表现出独特的基质特征，其结构细胞外基质（ECM）成分、ECM加工酶和分泌的信号蛋白如tgf - β2显著富集。它的蛋白质组组成，包括参与免疫反应的蛋白质，随着肿瘤大小的变化而变化，半色氨酸肽分析表明，PC中选择性ECM加工和肿瘤内蛋白水解水平升高。此外，肿瘤蛋白质组反映了典型的vhl驱动的代谢重编程，包括糖酵解和缺氧标记上调、有氧代谢抑制和脂肪酸代谢失调。丰富的免疫蛋白酶体、mhc - 1和炎性小体蛋白表明免疫反应活跃。肿瘤中富集的促血管生成因子部分延伸至前列腺癌。原发性和异时性ccRCC病例的比较揭示了VHL疾病中蛋白质组学肿瘤的可塑性。总之，我们的研究将PC描述为ccRCC边界上一个活跃的、富含信号的隔室，它对肿瘤进展和临床相关性具有潜在的影响，而不仅仅是一个结构支架。
{"title":"Proteomic characterization of the pseudocapsule of clear cell renal cell carcinoma in VHL disease reveals a distinct microenvironment at the tumor boundary zone","authors":"Tobias Feilen , Manuel Rogg , Grigor Andreev , Niko Pinter , Maximilian Wess , Anna L. Kössinger , Nastasja Diel , Elke Neumann-Haefelin , Athina Ganner , Markus Grabbert , Christoph Schell , Oliver Schilling","doi":"10.1016/j.neo.2025.101214","DOIUrl":"10.1016/j.neo.2025.101214","url":null,"abstract":"<div><div>Von Hippel-Lindau (VHL) disease describes a hereditary tumor predisposition syndrome, caused by germline mutations in the <em>VHL</em> tumor suppressor gene, resulting in the functional loss of the VHL protein (pVHL). pVHL loss translates into a pseudo-hypoxic state that drives clear cell renal cell carcinoma (ccRCC) development. ccRCC tumors frequently form a pseudocapsule (PC) at the tumor boundary. This study describes the first comprehensive proteomic analysis of the PC in ccRCC patients with hereditary <em>VHL</em> inactivation, revealing a distinctive matrisomal signature. We conducted a deep, mass spectrometry-based proteomic analysis of 130 formalin-fixed paraffin-embedded (FFPE) ccRCC samples, comprising 54 tumor, 45 PC, and 31 non-malignant adjacent tissue (NAT) specimens from 34 patients. The PC exhibited unique matrisomal features, with pronounced enrichment of structural extracellular matrix (ECM) components, ECM processing enzymes, and secreted signaling proteins such as TGFβ2. Its proteome composition, including proteins involved in immune response, varied with tumor size and semi-tryptic peptide analysis indicated selective ECM processing in the PC and elevated levels of proteolysis within the tumor. Further, tumor proteomes reflected canonical <em>VHL</em>-driven metabolic reprogramming, including upregulated glycolysis and hypoxia markers, suppressed aerobic metabolism, and dysregulated fatty acid metabolism. Enriched immunoproteasome, MHC-I, and inflammasome proteins indicated an active immune response. Pro-angiogenic factors enriched in the tumor partially extended into the PC. Comparison of primary vs metachronous ccRCC cases uncovered proteomic tumor plasticity in VHL disease. Together, our study delineates the PC as an active, signaling-rich compartment at the ccRCC boundary with potential implications for tumor progression and clinical relevance beyond a mere structural scaffold.</div></div>","PeriodicalId":18917,"journal":{"name":"Neoplasia","volume":"68 ","pages":"Article 101214"},"PeriodicalIF":7.7,"publicationDate":"2025-08-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144771807","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}
Pub Date : 2025-07-23DOI: 10.1016/j.neo.2025.101212
Aihetaimujiang Anwaier , Yuanyuan Qu , Shiqi Ye , Xi Tian , Shuxuan Zhu , Siqi Zhou , Guohai Shi , Yu Zhu , Hailiang Zhang , Dingwei Ye , Wenhao Xu
Renal angiomyolipoma (AML) encompasses benign variants (lipomatous [L-AML], myomatous [M-AML]) and epithelioid AML (eAML), a potentially malignant subtype associated with aggressive behavior. While TSC1/TSC2 mutations are frequent, the molecular drivers underlying eAML pathogenesis remain unclear. Whole-exome sequencing (WES) was performed on 35 AML samples (15 eAML, 10 L-AML, 10 M-AML) with matched germline controls. Driver genes were identified using OncodriveCLUST and MutSigCV. Validation was conducted on 71 FFPE samples integrating expression profiling and survival analysis. The finding suggested that TSC2 emerged as the most frequently mutated pathogenic gene in AML, exhibiting a mutation rate of 69 %. TSC2, POLDIP2, NEFH, and MUC2 emerged as potential driver genes across AML subtypes, whereas RHPN2, ASXL1, TOP3B, and USP35 showed subtype-specific mutations. Notably, distinct cytogenetic aberrations were observed among AML variants, including deletions at 3p26.3, 5p13.1, 6p22.1, and 11p11.11. Clonal evolution analysis suggested that l-AML and eAML, as well as M-AML and eAML, may originate from a common ancestral clone, retaining early mutations and acquiring additional alterations post-divergence. Low TSC2/POLDIP2 and high NEFH/MUC2 expression correlated with favorable survival in eAML patients. Importantly, lower TSC2/POLDIP2 expression also predicted superior response rates to Everolimus therapy. In conclusion, our study comprehensively delineates genomic distinctions and evolutionary trajectories among renal AML subtypes, establishing TSC2, POLDIP2, NEFH, and MUC2 as prognostic biomarkers and therapeutic predictors, facilitating precision medicine in eAML management.
{"title":"Genomic landscape and molecular evolutionary trajectories of renal epithelioid angiomyolipoma and benign angiomyolipoma","authors":"Aihetaimujiang Anwaier , Yuanyuan Qu , Shiqi Ye , Xi Tian , Shuxuan Zhu , Siqi Zhou , Guohai Shi , Yu Zhu , Hailiang Zhang , Dingwei Ye , Wenhao Xu","doi":"10.1016/j.neo.2025.101212","DOIUrl":"10.1016/j.neo.2025.101212","url":null,"abstract":"<div><div>Renal angiomyolipoma (AML) encompasses benign variants (lipomatous [L-AML], myomatous [M-AML]) and epithelioid AML (eAML), a potentially malignant subtype associated with aggressive behavior. While TSC1/TSC2 mutations are frequent, the molecular drivers underlying eAML pathogenesis remain unclear. Whole-exome sequencing (WES) was performed on 35 AML samples (15 eAML, 10 L-AML, 10 M-AML) with matched germline controls. Driver genes were identified using OncodriveCLUST and MutSigCV. Validation was conducted on 71 FFPE samples integrating expression profiling and survival analysis. The finding suggested that TSC2 emerged as the most frequently mutated pathogenic gene in AML, exhibiting a mutation rate of 69 %. TSC2, POLDIP2, NEFH, and MUC2 emerged as potential driver genes across AML subtypes, whereas RHPN2, ASXL1, TOP3B, and USP35 showed subtype-specific mutations. Notably, distinct cytogenetic aberrations were observed among AML variants, including deletions at 3p26.3, 5p13.1, 6p22.1, and 11p11.11. Clonal evolution analysis suggested that <span>l</span>-AML and eAML, as well as M-AML and eAML, may originate from a common ancestral clone, retaining early mutations and acquiring additional alterations post-divergence. Low TSC2/POLDIP2 and high NEFH/MUC2 expression correlated with favorable survival in eAML patients. Importantly, lower TSC2/POLDIP2 expression also predicted superior response rates to Everolimus therapy. In conclusion, our study comprehensively delineates genomic distinctions and evolutionary trajectories among renal AML subtypes, establishing TSC2, POLDIP2, NEFH, and MUC2 as prognostic biomarkers and therapeutic predictors, facilitating precision medicine in eAML management.</div></div>","PeriodicalId":18917,"journal":{"name":"Neoplasia","volume":"68 ","pages":"Article 101212"},"PeriodicalIF":4.8,"publicationDate":"2025-07-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144686787","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}
Pub Date : 2025-07-18DOI: 10.1016/j.neo.2025.101210
Qiaoting Hu , Xuefeng Wang , Yundan You , Jun Liu , Bin Lan , Fangfang Chen , Hong Wen , Haili Cheng , Weibin Zhuo , Ting Xu , Jingxian Zheng , Yuchuan Jiang , Xiaojie Wang , Jing Lin , Zengqing Guo , Sha Huang , Gang Chen , Yu Chen , Jingfeng Liu
The role of thymic epithelial cells (TECs) in eliminating self-reactive T cells through the presentation of self-antigens is well-established. However, it remains unclear whether TECs can eliminate tumor-reactive CD8+ T cells by presenting tumor antigens. In this study, we observed that CD73+ Granzyme B+ peripheral activated CD8+ T cells undergo apoptosis in the medullary region of the thymus in DEN-CCL4-induced spontaneous HCC mice, but not in the naïve control group. Mechanistically, HCC cells manipulate the thymus to recruit peripheral activated CD8+ T cells through the CCL19/CCL21-CCR7 axis. Additionally, TECs capture antigens from HCC cells for subsequent antigen presentation instead of de novo expressing tumor antigens. When tumor-associated CD8+ T cells homing to the thymus recognize the same tumor antigen presented by TECs, activation-induced cell death (AICD) is initiated in these T cells. Thymectomy redistributes CD8+ T cells into the tumor focus to suppress HCC growth. Alternatively, both inhibiting CCL19/CCL21 expression of thymic cells using an AMPK activator and blocking CCR7 on CD8+ T cells binding with ligands using Cmp2105 significantly reduces tumor-educated thymus dependent immune evasion. Our findings collectively demonstrate that HCC manipulates the thymus to trigger immune escape; pharmacologically targeting CCL19/CCL21-CCR7 axis to inhibit thymus homing can increase CD8+ T cells in the tumor microenvironment.
{"title":"Hepatocellular carcinoma escapes immune surveillance through deceiving thymus into recalling peripheral activated CD8+ T cells","authors":"Qiaoting Hu , Xuefeng Wang , Yundan You , Jun Liu , Bin Lan , Fangfang Chen , Hong Wen , Haili Cheng , Weibin Zhuo , Ting Xu , Jingxian Zheng , Yuchuan Jiang , Xiaojie Wang , Jing Lin , Zengqing Guo , Sha Huang , Gang Chen , Yu Chen , Jingfeng Liu","doi":"10.1016/j.neo.2025.101210","DOIUrl":"10.1016/j.neo.2025.101210","url":null,"abstract":"<div><div>The role of thymic epithelial cells (TECs) in eliminating self-reactive T cells through the presentation of self-antigens is well-established. However, it remains unclear whether TECs can eliminate tumor-reactive CD8<sup>+</sup> T cells by presenting tumor antigens. In this study, we observed that CD73<sup>+</sup> Granzyme B<sup>+</sup> peripheral activated CD8<sup>+</sup> T cells undergo apoptosis in the medullary region of the thymus in DEN-CCL<sub>4</sub>-induced spontaneous HCC mice, but not in the naïve control group. Mechanistically, HCC cells manipulate the thymus to recruit peripheral activated CD8<sup>+</sup> T cells through the CCL19/CCL21-CCR7 axis. Additionally, TECs capture antigens from HCC cells for subsequent antigen presentation instead of <em>de novo</em> expressing tumor antigens. When tumor-associated CD8<sup>+</sup> T cells homing to the thymus recognize the same tumor antigen presented by TECs, activation-induced cell death (AICD) is initiated in these T cells. Thymectomy redistributes CD8<sup>+</sup> T cells into the tumor focus to suppress HCC growth. Alternatively, both inhibiting CCL19/CCL21 expression of thymic cells using an AMPK activator and blocking CCR7 on CD8<sup>+</sup> T cells binding with ligands using Cmp2105 significantly reduces tumor-educated thymus dependent immune evasion. Our findings collectively demonstrate that HCC manipulates the thymus to trigger immune escape; pharmacologically targeting CCL19/CCL21-CCR7 axis to inhibit thymus homing can increase CD8<sup>+</sup> T cells in the tumor microenvironment.</div></div>","PeriodicalId":18917,"journal":{"name":"Neoplasia","volume":"67 ","pages":"Article 101210"},"PeriodicalIF":4.8,"publicationDate":"2025-07-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144661995","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}
Pub Date : 2025-07-17DOI: 10.1016/j.neo.2025.101211
Qing Zhou , Hongfei Yu , Anliang Dong , Jiani Yi , Jia Li , Xufan Li , Liyuan Zhou , Qiongzi Qiu , Bingjian Lu , Honghe Zhang , Weiguo Lu , Yi Sun , Pengyuan Liu , Yan Lu
Persistent infection with high-risk human papillomavirus (HPV) is the primary contributor to the development of cervical cancer. Although HPV oncoproteins E6 and E7 clearly trigger cervical tumorigenesis by inactivating p53 and Rb pathways, the downstream mediators of p53/Rb inactivation remain elusive. Here we report that CDT2, a subunit of Cullin-RING ligase 4 (CRL4), is significantly upregulated in cervical carcinoma tissues, which correlates with E6/E7 expression and poor patient survival. Mechanistically, E7-mediated Rb degradation upregulates E2F1, which in turn increases CDT2 transcription, whereas E6-mediated p53 degradation downregulates TRIM22, a novel E3 ligase for CDT2 degradation, leading to CDT2 accumulation to promote growth and survival of cervical cancer cells. Importantly, CDT2 depletion induces DNA aneuploidy and senescence via stabilization of histone lysine methyltransferase SET8, a CRL4CDT2 substrate, acting as a tumor suppressor. Collectively, the TRIM22-CDT2-SET8 axis is the key mediator of the p53/Rb signals in regulation of growth and survival of HPV-positive cervical carcinoma cells, Thus, CDT2 could serve as a prognostic biomarker and therapeutic target for these carcinomas.
{"title":"The TRIM22-CDT2 axis is the key mediator of the p53-Rb signals in growth control of HPV-positive cervical carcinoma cells","authors":"Qing Zhou , Hongfei Yu , Anliang Dong , Jiani Yi , Jia Li , Xufan Li , Liyuan Zhou , Qiongzi Qiu , Bingjian Lu , Honghe Zhang , Weiguo Lu , Yi Sun , Pengyuan Liu , Yan Lu","doi":"10.1016/j.neo.2025.101211","DOIUrl":"10.1016/j.neo.2025.101211","url":null,"abstract":"<div><div>Persistent infection with high-risk human papillomavirus (HPV) is the primary contributor to the development of cervical cancer. Although HPV oncoproteins E6 and E7 clearly trigger cervical tumorigenesis by inactivating p53 and Rb pathways, the downstream mediators of p53/Rb inactivation remain elusive. Here we report that CDT2, a subunit of Cullin-RING ligase 4 (CRL4), is significantly upregulated in cervical carcinoma tissues, which correlates with E6/E7 expression and poor patient survival. Mechanistically, E7-mediated Rb degradation upregulates E2F1, which in turn increases CDT2 transcription, whereas E6-mediated p53 degradation downregulates TRIM22, a novel E3 ligase for CDT2 degradation, leading to CDT2 accumulation to promote growth and survival of cervical cancer cells. Importantly, CDT2 depletion induces DNA aneuploidy and senescence via stabilization of histone lysine methyltransferase SET8, a CRL4<sup>CDT2</sup> substrate, acting as a tumor suppressor. Collectively, the TRIM22-CDT2-SET8 axis is the key mediator of the p53/Rb signals in regulation of growth and survival of HPV-positive cervical carcinoma cells, Thus, CDT2 could serve as a prognostic biomarker and therapeutic target for these carcinomas.</div></div>","PeriodicalId":18917,"journal":{"name":"Neoplasia","volume":"67 ","pages":"Article 101211"},"PeriodicalIF":4.8,"publicationDate":"2025-07-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144654614","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}
Pub Date : 2025-07-11DOI: 10.1016/j.neo.2025.101208
Suchita Suryakant Jadhav , Vipin Sharma , Aharon Lion , Lasser-Katz Efrat , Iftach Shaked , Galia Luboshits , Michael A. Firer
Introduction
Multiple Myeloma (MM) progresses over 2-3 decades through two pre-malignant stages (MGUS and SMM), culminating in clinically active disease. Given the limitations in acquiring sequential bone marrow (BM) samples from patients over this time frame, the mechanisms that compromise immunosurveillance and promote the development of MM remain
Methods
Balb/c mice inoculated with MOPC315.BM myeloma cells were followed over the next 220 days. Blood and bone marrow samples were collected on days 80, 150, and 220 post cell inoculation. Blood samples were used to monitor levels of paraprotein and whole blood cell counts. BM aspirates were used for deep immune profiling by flow cytometry and for T cell function assays.
Results
Blood analyses validated that the model reflects serological features of human MM. Analysis of BM samples revealed a biphasic behavior of T regulatory cells, Th17 cells, CD8+ cytotoxic T cells and NK cells, as well as skewing of CD4+ and CD8+ T memory cell subset distributionss, suggesting failure of an early anti-myeloma response, which is replaced by progressive immunosuppression, and dysfunction and exhaustion of CD8+ T cell tumor cytotoxicity.
Conclusion
Our new model is a flexible tool to investigate the early cellular interactions that initiate immunosuppression and MM disease progression. The model can also be used to test the efficacy of new therapeutic strategies.
{"title":"Biphasic behavior of T cell subsets reflects failure of early anti-myeloma response and leads to progressive T cell dysfunction","authors":"Suchita Suryakant Jadhav , Vipin Sharma , Aharon Lion , Lasser-Katz Efrat , Iftach Shaked , Galia Luboshits , Michael A. Firer","doi":"10.1016/j.neo.2025.101208","DOIUrl":"10.1016/j.neo.2025.101208","url":null,"abstract":"<div><h3>Introduction</h3><div>Multiple Myeloma (MM) progresses over 2-3 decades through two pre-malignant stages (MGUS and SMM), culminating in clinically active disease. Given the limitations in acquiring sequential bone marrow (BM) samples from patients over this time frame, the mechanisms that compromise immunosurveillance and promote the development of MM remain</div></div><div><h3>Methods</h3><div>Balb/c mice inoculated with MOPC315.BM myeloma cells were followed over the next 220 days. Blood and bone marrow samples were collected on days 80, 150, and 220 post cell inoculation. Blood samples were used to monitor levels of paraprotein and whole blood cell counts. BM aspirates were used for deep immune profiling by flow cytometry and for T cell function assays.</div></div><div><h3>Results</h3><div>Blood analyses validated that the model reflects serological features of human MM. Analysis of BM samples revealed a biphasic behavior of T regulatory cells, Th17 cells, CD8+ cytotoxic T cells and NK cells, as well as skewing of CD4+ and CD8+ T memory cell subset distributionss, suggesting failure of an early anti-myeloma response, which is replaced by progressive immunosuppression, and dysfunction and exhaustion of CD8+ T cell tumor cytotoxicity.</div></div><div><h3>Conclusion</h3><div>Our new model is a flexible tool to investigate the early cellular interactions that initiate immunosuppression and MM disease progression. The model can also be used to test the efficacy of new therapeutic strategies.</div></div>","PeriodicalId":18917,"journal":{"name":"Neoplasia","volume":"67 ","pages":"Article 101208"},"PeriodicalIF":4.8,"publicationDate":"2025-07-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144597484","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}
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