Neoplasia最新文献

{"title":"Genomic landscape and molecular evolutionary trajectories of renal epithelioid angiomyolipoma and benign angiomyolipoma","authors":"Aihetaimujiang Anwaier ,&nbsp;Yuanyuan Qu ,&nbsp;Shiqi Ye ,&nbsp;Xi Tian ,&nbsp;Shuxuan Zhu ,&nbsp;Siqi Zhou ,&nbsp;Guohai Shi ,&nbsp;Yu Zhu ,&nbsp;Hailiang Zhang ,&nbsp;Dingwei Ye ,&nbsp;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":"2025-10-01","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}

{"title":"Prkci activates Jak2/Stat3 signaling to promote tumor angiogenesis","authors":"Peng Li ,&nbsp;Guangshi Liu ,&nbsp;Wenbin Zhang ,&nbsp;Tao Li ,&nbsp;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":"2025-10-01","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}

{"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 ,&nbsp;Manuel Rogg ,&nbsp;Grigor Andreev ,&nbsp;Niko Pinter ,&nbsp;Maximilian Wess ,&nbsp;Anna L. Kössinger ,&nbsp;Nastasja Diel ,&nbsp;Elke Neumann-Haefelin ,&nbsp;Athina Ganner ,&nbsp;Markus Grabbert ,&nbsp;Christoph Schell ,&nbsp;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":"2025-10-01","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}

{"title":"A methyl-to-acetyl switch in H3K27 drives metabolic reprogramming and resistance to BRAFV600E inhibition in melanoma","authors":"Jiang Zhou ,&nbsp;Xinxin Chai ,&nbsp;Yi Zhu ,&nbsp;Zhi Huang ,&nbsp;Tingting Lin ,&nbsp;Zhen Hu ,&nbsp;Guangdi Chen ,&nbsp;Chi Luo ,&nbsp;Rutao Cui ,&nbsp;Jinghao Sheng","doi":"10.1016/j.neo.2025.101223","DOIUrl":"10.1016/j.neo.2025.101223","url":null,"abstract":"<div><div>The BRAF^V600E pathway and epigenetic machinery are central to melanoma pathogenesis. However, how these processes intersect and their potential for synthetic lethality remains unclear. Here, we identified a BRAF^V600E-driven epigenetic mechanism in melanoma that involves a H3K27 methylation-to-acetylation switch, facilitating metabolic adaptation to targeted therapies. Inhibition of BRAF^V600E downregulates the methyltransferase EZH2, leading to KDM6A-mediated removal of H3K27me3 and a subsequent increase in H3K27 acetylation (H3K27ac). This H3K27 methyl-to-acetyl conversion shifts chromatin from a repressive to an active state, thereby promoting gene transcription through the acetylation reader BRD4. Specifically, the KDM6A-H3K27ac-BRD4 axis upregulates PGC1α, a master regulator of mitochondrial metabolism, enabling melanoma cells to sustain oxidative metabolism and survive BRAF^V600E-targeted therapies. Blocking this H3K27 methyl-to-acetyl switch disrupted metabolic adaptation and sensitized melanoma cells to BRAF^V600E inhibition. In conclusion, we revealed an epigenetic and metabolic reprogramming mechanism that enables melanoma to survive the treatment with BRAF^V600E inhibitors, presenting druggable targets within the H3K27 modification pathway that could enhance the efficacy of BRAF-targeted therapies in melanoma patients.</div></div>","PeriodicalId":18917,"journal":{"name":"Neoplasia","volume":"68 ","pages":"Article 101223"},"PeriodicalIF":7.7,"publicationDate":"2025-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144892261","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":"Screening and identification of HLA-A2-restricted neoepitopes for immunotherapy in endocrine therapy-resistant breast cancer","authors":"Mingshuang Wang ,&nbsp;Liwei Pang ,&nbsp;Yingjie Sun ,&nbsp;Jingjing Han ,&nbsp;Jiani Fan ,&nbsp;Wenhui Shen ,&nbsp;Xiaonan Hu ,&nbsp;Bingqian Yang ,&nbsp;Haoming Ning ,&nbsp;Yanan Kong ,&nbsp;Duo Li ,&nbsp;Wenshan Zhao ,&nbsp;Ranran Shi ,&nbsp;Ling Ran ,&nbsp;Yuanming Qi ,&nbsp;Yahong Wu","doi":"10.1016/j.neo.2025.101200","DOIUrl":"10.1016/j.neo.2025.101200","url":null,"abstract":"<div><div>Endocrine therapy has shown significant clinical efficacy in estrogen receptor alpha (ERα)-positive breast cancer management, but the emergence of therapy-resistant mutations significantly undermines treatment outcomes, frequently leading to disease progression and metastasis. Among these resistance mechanisms, mutations in the ESR1 gene are particularly prevalent, detectable in 76% of endocrine therapy-resistant tumor specimens. The identification of immunogenic neoepitopes derived from mutant ESR1 offers a promising therapeutic avenue for patients with endocrine therapy-resistant breast cancer. In this study, we systematically investigated the mutational landscape of ESR1 across various cancer types, with particular emphasis on mutation frequency and spectrum analysis. Our findings revealed that non-synonymous ESR1 mutations predominantly occurred in breast cancer, clustering at four distinct hotspot sites: K303, E380, Y537 and D538. We further characterized the mutation prevalence at these hotspots across different breast cancer subtypes. Through comprehensive screening, we identified eight human leukocyte antigen (HLA)-A*0201 restricted immunogenic neoepitopes derived from ESR1 hotspot mutations. These neoepitopes demonstrated the capacity to elicit specific cytotoxic T lymphocytes (CTLs) responses both <em>in vitro</em> and <em>in vivo</em>. The induced CTLs exhibited specific recognition and cytotoxic activity against both T2A2 cells loaded with mutant neoepitopes and HLA-A*0201-positive breast cancer cells transfected with minigene encoding mutant neoepitopes. Notably, adoptive transfer of T cells primed with a peptide pool containing these eight neoepitopes significantly suppressed tumor growth and enhanced CD8⁺ T cells infiltration within tumor tissue. These findings suggest that the identified neoepitopes represent promising candidates for the development of tumor shared neoantigen vaccines.</div></div>","PeriodicalId":18917,"journal":{"name":"Neoplasia","volume":"67 ","pages":"Article 101200"},"PeriodicalIF":4.8,"publicationDate":"2025-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144338697","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":"Comparative effects of combustible cigarette versus electronic cigarette exposures on KRAS mutant lung cancer promotion","authors":"Walter V. Velasco ,&nbsp;Maria T. Grimaldo ,&nbsp;Nastaran Karimi ,&nbsp;Michael J. Clowers ,&nbsp;Avantika Krishna ,&nbsp;Ranran Wu ,&nbsp;Rahmah Ejaz ,&nbsp;Bo Yuan ,&nbsp;Segundo del Aguila ,&nbsp;Iman Bouchelkia ,&nbsp;Javier Eduardo Moreno Barragan ,&nbsp;Katherine E. Larsen ,&nbsp;Yasmina Rezai ,&nbsp;Farbod Khalaj ,&nbsp;Kyler Mitra ,&nbsp;Carlos Reyna Rodriguez ,&nbsp;Ricardo Millares ,&nbsp;Angelica Baca de Anda ,&nbsp;Susana Castro-Pando ,&nbsp;Umesh C. Karandikar ,&nbsp;Seyed Javad Moghaddam","doi":"10.1016/j.neo.2025.101185","DOIUrl":"10.1016/j.neo.2025.101185","url":null,"abstract":"<div><div>Despite the emerging public health concern related to the use of electronic cigarette vapors (ECV), its impact on lung cancer is poorly understood. We assessed the effect of ECV on lung tumorigenesis in a mouse model of lung adenocarcinoma. Mice were exposed to either room air, combustible cigarette smoke (CCS), or ECV 2 hours daily for 8 weeks at which lung samples were harvested and studied for different outcomes. We found that CCS, but not ECV, led to a significant increase in tumor burden. Immunophenotyping of both CCS- and ECV-exposed lungs displayed pronounced pro-tumor immunosuppressive phenotypes, characterized by significantly decreased CD4+ IFNγ+ and CD8+ GZMB+ T cells along with an elevated CD4+ FOXP3+ regulatory T cells. However, differential changes in myeloid cells were observed between CCS and ECV-exposed lungs. A microbiome profiling of matched stool and lung samples showed differences in the relative abundance of lung <em>Pseudomonadotas</em>, while gut <em>Bacillota</em>, particularly <em>Turicibacter,</em> and <em>Ileibacterium</em> were increased by CCS and ECV. We conclude that both CCS and ECV exposure under the applied regimen lead to a protumor immune suppressive lung microenvironment although with different magnitudes and slightly different phenotypes that might explain their differential effects on tumor burden warranting further studies.</div></div>","PeriodicalId":18917,"journal":{"name":"Neoplasia","volume":"67 ","pages":"Article 101185"},"PeriodicalIF":4.8,"publicationDate":"2025-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144272344","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":"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 ,&nbsp;Hongfei Yu ,&nbsp;Anliang Dong ,&nbsp;Jiani Yi ,&nbsp;Jia Li ,&nbsp;Xufan Li ,&nbsp;Liyuan Zhou ,&nbsp;Qiongzi Qiu ,&nbsp;Bingjian Lu ,&nbsp;Honghe Zhang ,&nbsp;Weiguo Lu ,&nbsp;Yi Sun ,&nbsp;Pengyuan Liu ,&nbsp;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^CDT2 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":"2025-09-01","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}

{"title":"Hepatocellular carcinoma escapes immune surveillance through deceiving thymus into recalling peripheral activated CD8+ T cells","authors":"Qiaoting Hu ,&nbsp;Xuefeng Wang ,&nbsp;Yundan You ,&nbsp;Jun Liu ,&nbsp;Bin Lan ,&nbsp;Fangfang Chen ,&nbsp;Hong Wen ,&nbsp;Haili Cheng ,&nbsp;Weibin Zhuo ,&nbsp;Ting Xu ,&nbsp;Jingxian Zheng ,&nbsp;Yuchuan Jiang ,&nbsp;Xiaojie Wang ,&nbsp;Jing Lin ,&nbsp;Zengqing Guo ,&nbsp;Sha Huang ,&nbsp;Gang Chen ,&nbsp;Yu Chen ,&nbsp;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⁺ 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 <em>de novo</em> 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.</div></div>","PeriodicalId":18917,"journal":{"name":"Neoplasia","volume":"67 ","pages":"Article 101210"},"PeriodicalIF":4.8,"publicationDate":"2025-09-01","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}

{"title":"The immune response against cancer is modulated by stromal cell fibronectin","authors":"Alexander Lubosch ,&nbsp;Lauren Pitt ,&nbsp;Caren Zoeller ,&nbsp;Franziska Wirth ,&nbsp;Tarik Exner ,&nbsp;Barbara Steigenberger ,&nbsp;Guido Wabnitz ,&nbsp;Jutta Schroeder-Braunstein ,&nbsp;Inaam A. Nakchbandi","doi":"10.1016/j.neo.2025.101196","DOIUrl":"10.1016/j.neo.2025.101196","url":null,"abstract":"<div><div>Cancer-associated fibroblasts remain poorly understood, with some of them originating from the bone marrow. We therefore took advantage of the diversity of bone marrow stromal cells to shed light on how fibroblasts modulate cancer growth.</div><div>In two murine cancer models, adding these fibroblasts to tumor cells resulted in smaller lesions. Suppression was enhanced by pretreatment with fibronectin, while genetic deletion of fibronectin in a small subpopulation of stromal cells expressing osterix/<em>sp7</em> restored growth. The suppressive stromal population showed two more characteristics: the absence of CD31/<em>pecam1</em> and CD105/<em>endoglin</em>. However, only a decrease in CD105/<em>ENDOGLIN</em> in melanoma patients translated in improved survival. Mechanistically, fibronectin or fibronectin fragments activate integrin α5β1 and TLR4 and increase chemokine production by stromal cells ultimately leading to enhanced recruitment and activity of Ly6G⁺ myeloid cells without T-cell involvement.</div><div>This work thus characterizes a beneficial interaction between stromal cells and neutrophils enhancing the immune response against early cancer.</div></div>","PeriodicalId":18917,"journal":{"name":"Neoplasia","volume":"67 ","pages":"Article 101196"},"PeriodicalIF":4.8,"publicationDate":"2025-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144513939","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":"Cancer-associated VEGFR2R1032Q sustains receptor activation also by promoting ligand-independent hetero-dimerization with co-expressed wild-type VEGFR2 and translocation into lipid rafts","authors":"Cosetta Ravelli ,&nbsp;Michela Corsini ,&nbsp;Roberto Bresciani ,&nbsp;Angela M. Rizzo ,&nbsp;Luca Zammataro ,&nbsp;Paola A. Corsetto ,&nbsp;Elisabetta Grillo ,&nbsp;Stefania Mitola","doi":"10.1016/j.neo.2025.101195","DOIUrl":"10.1016/j.neo.2025.101195","url":null,"abstract":"<div><div>The substitution R1032Q is the most frequent non-synonymous mutation of the vascular endothelial growth factor receptor 2 (VEGFR2) in cancer patients, classified as a loss-of-function variant. Here we characterize the molecular bases of its role in cancer, demonstrating that it lacks significant activity and pro-oncogenic effects in VEGFR2-negative tumor cells, while being able to sustain the tumorigenic potential of VEGFR2-positive cancer cells. By implementing a cell model that allows expression of either VEGFR2^R1032Q alone or in combination with VEGFR2^WT, we showed that the effects of mutated VEGFR2 are at least in part due to the ability of VEGFR2^R1032Q to form functional heterodimers with co-expressed VEGFR2^WT that result in increased kinase activity and receptor phosphorylation. This was associated with reduced mobility of the receptor on the membrane, linked to its translocation into detergent-resistant membrane (DRM) domains (e.g. lipid rafts), which showed alterations in lipid compositions and structure. These data shed light on a novel oncogenic mechanism of activation of VEGFR2, clarifying the paradoxical loss-of-function nature of the substitution R1032Q of VEGFR2.</div></div>","PeriodicalId":18917,"journal":{"name":"Neoplasia","volume":"67 ","pages":"Article 101195"},"PeriodicalIF":4.8,"publicationDate":"2025-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144280019","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}