Neoplasia最新文献

{"title":"Anti-PD1 prolongs the response of PI3K and farnesyl transferase inhibition in HRAS- and PIK3CA-mutant head and neck cancers","authors":"Dinesh Babu Manikandan ,&nbsp;Sankar Jagadeeshan ,&nbsp;Sooraj Mathukkada ,&nbsp;Raghda Abu Shareb ,&nbsp;Manu Prasad ,&nbsp;Liju Vijaya Steltar Belsamma ,&nbsp;Divyasree Marripati ,&nbsp;Noga Erez ,&nbsp;Monica Wainer ,&nbsp;Amit Geva ,&nbsp;Danielle Raviv ,&nbsp;Irit Allon ,&nbsp;Luc GT Morris ,&nbsp;Gloria H Su ,&nbsp;Hai Wang ,&nbsp;Ari J Rosenberg ,&nbsp;Linda Kessler ,&nbsp;Francis Burrows ,&nbsp;Moshe Elkabets","doi":"10.1016/j.neo.2025.101157","DOIUrl":"10.1016/j.neo.2025.101157","url":null,"abstract":"<div><h3>Background</h3><div>Tipifarnib, a farnesyl transferase inhibitor, has shown promising response in the treatment of <em>HRAS</em>-mutant HNSCC in the clinic, and in combination with a PI3K inhibitor in <em>PIK3CA</em>-mutant mouse models; however, the involvement of antitumor immunity in the efficacy of tipifarnib has not yet been investigated. This study aimed to evaluate the involvement of antitumor immunity in the efficacy of tipifarnib in <em>HRAS</em>- or <em>PIK3CA</em>-mutant HPV-positive and HPV-negative head and neck cancer murine models.</div></div><div><h3>Methods</h3><div>To investigate the role of antitumor immunity, we compared the efficacy of tipifarnib in immune-intact C57BL/6 mice and immunodeficient NSG mice. Histopathological analyses were conducted to evaluate PD-L1 expression and the activation of key signaling pathways. Additionally, the synergistic potential of tipifarnib with the PI3Kα inhibitor alpelisib (BYL719) was assessed <em>in vitro</em> and <em>in vivo</em>. Immunohistochemical analysis was performed to examine the infiltration of CD8⁺ <em>T</em> cells, and anti-PD1 treatment was tested to evaluate its potential to prolong progression-free survival.</div></div><div><h3>Results</h3><div>In the HPV-positive <em>HRAS</em>-mutant HNSCC model, the antitumor efficacy of tipifarnib was primarily dependent on CD8⁺ <em>T</em> cell activity, whereas in HPV-negative cancers, the contribution of antitumor immunity was less pronounced. Tipifarnib treatment upregulated PD-L1 expression, potentially inhibiting T cell antitumor activity and inducing hyperactivation of the AKT pathway, which mitigated MAPK inhibition and promoted cell proliferation. Blocking the PI3K pathway with alpelisib demonstrated synergistic antitumor effects in all models. The combination of tipifarnib and alpelisib exhibited greater efficacy in immune-intact mice than in immunodeficient mice, and was accompanied by increased CD8⁺ <em>T</em> cell infiltration. Adding anti-PD1 treatment to the tipifarnib/alpelisib combination further prolonged progression-free survival in tumor-bearing mice.</div></div><div><h3>Conclusion</h3><div>These findings underscore the critical role of antitumor immunity, particularly CD8⁺ <em>T</em> cell activity, in the efficacy of tipifarnib alone and in combination with alpelisib. The triple combination of tipifarnib, alpelisib, and anti-PD1 treatment showed superior antitumor activity and extended survival in preclinical models, suggesting its potential as a therapeutic strategy for HNSCC patients with <em>HRAS</em>- and <em>PIK3CA</em>-mutation.</div></div>","PeriodicalId":18917,"journal":{"name":"Neoplasia","volume":"63 ","pages":"Article 101157"},"PeriodicalIF":4.8,"publicationDate":"2025-03-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143674768","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Kv11.1-dependent senescence activates a lethal immune response via tumor necrosis factor alpha","authors":"Maedeh Vakili Saatloo ,&nbsp;Davide Delisi ,&nbsp;Najmeh Eskandari ,&nbsp;Carsten Krieg ,&nbsp;Saverio Gentile","doi":"10.1016/j.neo.2025.101148","DOIUrl":"10.1016/j.neo.2025.101148","url":null,"abstract":"<div><div>Understanding the complex relationship between cancer and immune surveillance is essential for leveraging the immune system to control tumor growth. In our study, we discovered that activating the Kv11.1 potassium channel in ER+ breast cancer cells induces a senescent phenotype, which in turn triggers a potent immune response against these senescent cells. Specifically, we found that the senescence-associated secretory phenotype (SASP) plays a crucial role in activating CD4+ <em>T</em>-helper 1 (Th1) cells and memory T cell phenotypes. This activation led to the release of tumor necrosis factor-alpha (TNFα), which induced the death of senescent breast cancer cells, independent of their resistance to endocrine therapy. Our findings suggest that Kv11.1 channel-induced cellular senescence in ER+ breast cancer cells is a key mechanism in immune surveillance, driving a lethal immune response through TNFα. These results highlight the potential immunomodulatory role of Kv11.1 activation in ER-positive breast cancer and provide a foundation for future therapeutic investigations.</div></div>","PeriodicalId":18917,"journal":{"name":"Neoplasia","volume":"63 ","pages":"Article 101148"},"PeriodicalIF":4.8,"publicationDate":"2025-03-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143674769","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Targeting BARD1 suppresses a Myc-dependent transcriptional program and tumor growth in pancreatic ductal adenocarcinoma","authors":"Sohum Patel ,&nbsp;Eleanor Jenkins ,&nbsp;Rutuj P Kusurkar ,&nbsp;Sherry Lee ,&nbsp;Wei Jiang ,&nbsp;Avinoam Nevler ,&nbsp;Matthew McCoy ,&nbsp;Michael J Pishvaian ,&nbsp;Rosalie C Sears ,&nbsp;Jonathan R Brody ,&nbsp;Charles J Yeo ,&nbsp;Aditi Jain","doi":"10.1016/j.neo.2025.101152","DOIUrl":"10.1016/j.neo.2025.101152","url":null,"abstract":"<div><div>Pancreatic ductal adenocarcinoma (PDAC) remains one of the deadliest cancers demanding better and more effective therapies. BARD1 or BRCA1-Associated -Ring Domain-1 plays a pivotal role in homologous recombination repair (HRR). However, its function and the underlying molecular mechanisms in PDAC are still not fully elucidated. Here, we demonstrate that BARD1 is overexpressed in PDAC and its genetic inhibition suppresses c-Myc and disrupts c-Myc dependent transcriptional program. Mechanistically, BARD1 stabilizes c-Myc through ubiquitin–proteasome system by regulating FBXW7. Importantly, targeting BARD1 using either siRNAs or CRISPR/Cas9 deletion blocks PDAC growth <em>in vitro</em> and <em>in vivo</em>, without any signs of toxicity to mice. Using a focused drug library of 477 DNA damage response compounds, we also found that BARD1 inhibition enhances therapeutic efficacy of several clinically relevant agents (fold changes ≥4), including PARPi, in HRR proficient PDAC cells. These data uncover BARD1 as an attractive therapeutic target for HRR proficient PDAC.</div></div>","PeriodicalId":18917,"journal":{"name":"Neoplasia","volume":"63 ","pages":"Article 101152"},"PeriodicalIF":4.8,"publicationDate":"2025-03-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143632197","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Granulocyte-macrophage colony-stimulating factor for newly diagnosed glioblastoma","authors":"Caineng Cao ,&nbsp;Le Wang ,&nbsp;Feng Jiang ,&nbsp;Qifeng Jin ,&nbsp;Ting Jin ,&nbsp;Shuang Huang ,&nbsp;Qiaoying Hu ,&nbsp;Yuanyuan Chen ,&nbsp;Yongfeng Piao ,&nbsp;Yonghong Hua ,&nbsp;Xinglai Feng ,&nbsp;Yi Zhou ,&nbsp;Xiaozhong Chen","doi":"10.1016/j.neo.2025.101156","DOIUrl":"10.1016/j.neo.2025.101156","url":null,"abstract":"<div><h3>Background</h3><div>There is a clear need to improve the efficiency of therapeutic strategy for patients with newly diagnosed glioblastoma (GBM). The purpose of this study was to evaluate the feasibility of hypofractionated intensity-modulated radiation therapy (IMRT), temozolomide and granulocyte-macrophage colony-stimulating factor (GM-CSF) for patients with newly diagnosed GBM.</div></div><div><h3>Methods</h3><div>Patients were treated with hypofractionated IMRT (15 × 3.5Gy to the high-risk region and 15 × 3.0Gy to the low-risk region), temozolomide (75 mg per square meter of body-surface area per day, from 1 week before the beginning of radiotherapy to the last day of radiotherapy) and GM-CSF [200μg (equivalent to 125 μg/m² calculated dose) subcutaneously injected daily for 2 weeks, starting from the second week of radiotherapy]. The primary endpoint was 6-month progression free survival (PFS).</div></div><div><h3>Results</h3><div>Between June 2016 and Feburary 2020, 41 patients were enrolled. During concomitant chemoradiotherapy, no grade 3 or 4 hematologic toxicities were observed and grade 3 non-hematologic toxicities were documented in 5 patients (12.2 %) due to GM-CSF. All patients completed both radiotherapy and concomitant temozolomide as planned. Only five patients (12.2 %) discontinued concomitant GM-CSF because of toxicity. At a median follow-up of 33.1 months (IQR 23.0-51.2), the 6-month PFS rate was 68.3 % (95 % CI: 54.0-82.6). The median overall survival of all patients was 16.7 months (95 % CI: 10.5-22.9). Compared with pre-GM-CSF, the concentrations of TNF-α (<em>p</em> = 1.9615E-10) and IL-18 (<em>p</em> = 6.8467E-8) were increased after GM-CSF, while the proportion of CD19 (<em>p</em> = 0.000015), the concentrations of IgG (<em>p</em> = 0.000015) and CXCL12 (<em>p</em> = 0.000257) were decreased.</div></div><div><h3>Conclusions</h3><div>The combination of hypofractionated IMRT, temozolomide and GM-CSF for GBM was feasible and safe.</div></div><div><h3>Trial Registration</h3><div>ClinicalTrials.gov Identifier: NCT02663440.</div></div>","PeriodicalId":18917,"journal":{"name":"Neoplasia","volume":"63 ","pages":"Article 101156"},"PeriodicalIF":4.8,"publicationDate":"2025-03-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143632214","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Targeting PAR1 activation in JAK2V617F-driven philadelphia-negative myeloproliferative neoplasms: Unraveling its role in thrombosis and disease progression","authors":"İldeniz USLU-BIÇAK ,&nbsp;Meliha NALÇACI ,&nbsp;Selçuk SÖZER","doi":"10.1016/j.neo.2025.101153","DOIUrl":"10.1016/j.neo.2025.101153","url":null,"abstract":"<div><div>Philadelphia chromosome-negative myeloproliferative neoplasms (Ph^-MPNs) are clonal disorders marked by high morbidity and mortality, driven by uncontrolled myeloid proliferation from hematopoietic stem/progenitor cells (HSCs) and associated with a significant risk of thrombosis. This study explored the relationship between <em>JAK2</em>V617F and protease-activated receptor 1 (PAR1) by examining <em>PAR1</em> expression and activation across various hematopoietic stem/progenitor cell (HSPC) subgroups, assessing their contribution to the hypercoagulable state in Ph^-MPNs.</div><div>We investigated the effects of thrombin, a PAR1 antagonist (vorapaxar), and a JAK2 inhibitor (ruxolitinib) on Ph^-MPN cells. Mononuclear cells (MNCs) were isolated from Ph-MPN patients (<em>n</em> = 18), cord blood (CB) samples (<em>n</em> = 5) and healthy volunteers (<em>n</em> = 11). Specific subpopulations were sorted and analyzed for PAR1 expression and <em>JAK2</em>V617F status using qRT-PCR. <em>PAR1</em> expression changes, along with other PAR pathway-related genes, were assessed post-treatment.</div><div>Our results revealed that most PAR1⁺ cells (∼95 %) co-expressed CD34⁺, with a smaller JAK2V617F⁺ PAR1⁺ population lacking CD34. PAR1 expression was significantly higher in Ph-MPN MNCs compared to CB (<em>p</em> = 0.0005), particularly in EMP, HSC/EPC, and EPC subsets. Thrombin treatment reduced surface PAR1 expression, while PAR1 antagonist treatment further decrease the expression level. Combined PAR1 antagonist and ruxolitinib treatment significantly downregulated <em>PAR1</em> expression (<em>p</em> &lt; 0.0001), and several PAR-pathway-related genes were notably downregulated after treatment.</div><div>This study highlights that elevated PAR1 expression in primitive hematopoietic subpopulations is linked to disease progression and thrombosis in Ph^-MPNs, suggesting PAR1 as a potential therapeutic target. Combining PAR1 antagonists with JAK2 inhibitors shows promise in reducing PAR1 expression and mitigating thrombotic events in Ph^-MPN patients.</div></div>","PeriodicalId":18917,"journal":{"name":"Neoplasia","volume":"63 ","pages":"Article 101153"},"PeriodicalIF":4.8,"publicationDate":"2025-03-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143620539","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"LSD1+8a is an RNA biomarker of neuroendocrine prostate cancer","authors":"Anbarasu Kumaraswamy ,&nbsp;Rahul Mannan ,&nbsp;Olivia A. Swaim ,&nbsp;Eva Rodansky ,&nbsp;Xiao-Ming Wang ,&nbsp;Aaron Udager ,&nbsp;Rohit Mehra ,&nbsp;Hui Li ,&nbsp;Colm Morrissey ,&nbsp;Eva Corey ,&nbsp;Michael C. Haffner ,&nbsp;Peter S. Nelson ,&nbsp;Arul M. Chinnaiyan ,&nbsp;Joel A. Yates ,&nbsp;Joshi J. Alumkal","doi":"10.1016/j.neo.2025.101151","DOIUrl":"10.1016/j.neo.2025.101151","url":null,"abstract":"<div><h3>Background</h3><div>Lysine-specific demethylase 1 (LSD1) is a histone demethylase and regulator of differentiation, including in cancer. A neuronal-specific isoform of <em>LSD1</em>—<em>LSD1+8a</em>—has been shown to play a key role in promoting neuronal differentiation in the developing brain. We previously determined that <em>LSD1+8a</em> transcripts were detected in an aggressive subtype of prostate cancer harboring a neuronal program—neuroendocrine prostate cancer (NEPC)—but not in prostate adenocarcinomas harboring a glandular program. However, the number of samples examined was limited.</div></div><div><h3>Methods</h3><div>Using a large collection of prostate cancer patient cell lines and patient-derived xenografts (PDXs), we measured LSD1+8a using quantitative polymerase chain reaction (qPCR), RNA <em>in situ</em> hybridization (RNA-ISH), and protein detection methods. We then validated our findings using an independent cohort of patient tumor samples.</div></div><div><h3>Results</h3><div><em>LSD1+8a</em> mRNA expression was detected in every NEPC cell line and PDX examined by qPCR and RNA-ISH but in none of the prostate adenocarcinomas. We validated the RNA-ISH results in patient tumors, confirming that <em>LSD1+8a</em> was expressed in all NEPC tumors but in none of the adenocarcinomas. Finally, we generated a rabbit monoclonal antibody specific to LSD1+8a protein and confirmed its specificity using normal neuronal tissue samples. However, LSD1+8a protein was not detectable in NEPC tumors—likely due to the substantially lower levels of <em>LSD1+8a</em> mRNA in NEPC tumors vs. normal neuronal tissues.</div></div><div><h3>Conclusions</h3><div>Measuring <em>LSD1+</em>8a mRNA is a sensitive and specific method for the diagnosis of NEPC, which is often challenging.</div></div>","PeriodicalId":18917,"journal":{"name":"Neoplasia","volume":"63 ","pages":"Article 101151"},"PeriodicalIF":4.8,"publicationDate":"2025-03-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143620538","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"O-GlcNAc-modified HOXA9 suppresses ferroptosis via promoting UBR5-mediated SIRT6 degradation in nasopharyngeal carcinoma","authors":"Huai Liu ,&nbsp;Yingzhou Fu ,&nbsp;Ling Tang ,&nbsp;Bo Song ,&nbsp;Wangning Gu ,&nbsp;Hongmin Yang ,&nbsp;Tengfei Xiao ,&nbsp;Hui Wang ,&nbsp;Pan Chen","doi":"10.1016/j.neo.2025.101142","DOIUrl":"10.1016/j.neo.2025.101142","url":null,"abstract":"<div><h3>Background</h3><div>Nasopharyngeal carcinoma (NPC) is the most common malignancy of the nasopharynx. Ferroptosis induction shows anti-tumor activities in cancers including NPC. Elucidating the regulatory mechanism of ferroptosis is crucial for developing targeted therapeutic strategies for NPC.</div></div><div><h3>Methods</h3><div>The GEO dataset (GSE68799) was used to analyze HOXA9 expression in NPC. Cell viability, levels of MDA, total iron, Fe²⁺ and GSH, and lipid peroxidation were examined for ferroptosis evaluation. O-GlcNAcylation levels on HOXA9 and ubiquitination levels on SIRT6 were detected by immunoprecipitation. ChIP and luciferase assays were applied for determining the interaction of HOXA9 and UBR5. The interaction between UBR5 and SIRT6, OGT and HOXA9 were evaluated by Co-IP assays. A subcutaneous NPC mouse model was established to explore whether knockdown of HOXA9 or UBR5 regulates tumor growth <em>in vivo</em>.</div></div><div><h3>Results</h3><div>HOXA9 was highly expressed in NPC, and knockdown of HOXA9 elevated total iron, Fe²⁺ and lipid peroxidation and reduced GSH and NPC cell viability. O-GlcNAcylation stabilized HOXA9 and facilitated its nuclear translocation in NPC cells. HOXA9 directly bound to UBR5 promoter to increase its expression, thus accelerating ubiquitination and degradation of SIRT6. HOXA9 restrained ferroptosis via promoting UBR5 expression, and UBR5 suppressed ferroptosis through promotion of SIRT6 ubiquitination and degradation. Knockdown of HOXA9 or UBR5 promoted ferroptosis and inhibited NPC growth in mice.</div></div><div><h3>Conclusion</h3><div>O-GlcNAc-modified HOXA9 inhibits ferroptosis by enhancing UBR5 expression and ubiquitination and degradation of SIRT6 in NPC cells, thus accelerating NPC progression. Our study provides potential therapeutic targets for NPC treatment.</div></div>","PeriodicalId":18917,"journal":{"name":"Neoplasia","volume":"62 ","pages":"Article 101142"},"PeriodicalIF":4.8,"publicationDate":"2025-03-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143601636","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"HRP2 regulating MICU1-mediated Ca2+ overload to dictate chemoresistance of multiple myeloma","authors":"Qian Li ,&nbsp;Ziyi Peng ,&nbsp;Li Lin ,&nbsp;Zhiying Zhang ,&nbsp;Jing Ma ,&nbsp;Lin Chen ,&nbsp;Su Liu ,&nbsp;Shuang Gao ,&nbsp;Linchuang Jia ,&nbsp;Jingjing Wang ,&nbsp;Zeng Cao ,&nbsp;Xingli Zhao ,&nbsp;Zhiqiang Liu ,&nbsp;Yafei Wang","doi":"10.1016/j.neo.2025.101150","DOIUrl":"10.1016/j.neo.2025.101150","url":null,"abstract":"<div><div>Despite the efficacy of bortezomib (BTZ)-based chemotherapy in treating multiple myeloma (MM) patients, chemoresistance occurs frequently over time, particularly in individuals exhibiting an initial positive response to BTZ therapy. In this study, we established BTZ-resistant MM cells and identified that suppressed expression of the hepatoma-derived growth factor (HDGF)-related protein-2 (HRP2) was a key determinant of chemoresistance in MM cells. Manipulating HRP2 expression remodeled the chemosensitivity of MM cells in vitro and in vivo. Clinically, lower expression of HRP2 predicted a shorter survival rate in MM patients receiving BTZ-based regimens. Mechanistically, HRP2 depletion resulted in elevated acetylation modifications of histone 3 at lysine 27 (H3K27Ac), and enhanced chromatin accessibility as well as transcriptional elongation of mitochondrial calcium uptake 1(MICU1) gene, thus promoting the expression of MICU1 gene and alleviating calcium (Ca²⁺) overload and excessive reactive oxygen species (ROS) induced mitochondria damage and apoptosis in MM cells. Thereby, MICU1 suppression improved BTZ sensitivity in vitro and relieved tumor burden in a mouse model of MM. Similarly, elevated MICU1 expression was observed in the B220⁺CD19⁺ B cells from HRP2-knockout mice and significantly correlated with poor prognosis in the clinic. Thus, our study elucidates the previously unrecognized epigenetic role of HRP2 in regulating calcium homeostasis of MM cells, providing new theoretical insights into the mechanisms underlying the development of drug resistance in multiple myeloma.</div></div>","PeriodicalId":18917,"journal":{"name":"Neoplasia","volume":"62 ","pages":"Article 101150"},"PeriodicalIF":4.8,"publicationDate":"2025-03-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143578121","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Combining the RCAS/tv-a retrovirus and CRISPR/Cas9 gene editing systems to generate primary mouse models of diffuse midline glioma","authors":"Sophie R. Wu ,&nbsp;Julianne Sharpe ,&nbsp;Joshua Tolliver ,&nbsp;Abigail J. Groth ,&nbsp;Reid Chen ,&nbsp;María E. Guerra García ,&nbsp;Vennesa Valentine ,&nbsp;Nerissa T. Williams ,&nbsp;Sheeba Jacob ,&nbsp;Zachary J. Reitman","doi":"10.1016/j.neo.2025.101139","DOIUrl":"10.1016/j.neo.2025.101139","url":null,"abstract":"<div><div>Diffuse midline gliomas (DMGs) are lethal brain tumors that arise in children and young adults, resulting in a median survival of less than two years. Genetically engineered mouse models (GEMMs) are critical to studying tumorigenesis and tumor-immune interactions, which may inform new treatment approaches. However, current midline glioma GEMM approaches are limited in their ability to multiplex perturbations and/or target specific cell lineages in the brain for genetic manipulation. Here, we combined the RCAS/tv-a avian retrovirus system and CRISPR/Cas9 genetic engineering to drive midline glioma formation in mice. CRISPR/Cas9-based disruption of <em>Trp53</em>, a tumor suppressor that is frequently disrupted in midline gliomas, along with the oncogene PDGF-B resulted in high grade tumor formation with moderate latency (median time to tumor formation of 12 weeks). We confirmed CRISPR-mediated <em>Trp53</em> disruption using next-generation sequencing (NGS) and immunohistochemistry (IHC). Next, we disrupted multiple midline glioma tumor suppressor genes (<em>Trp53, Pten, Atm, Cdkn2a</em>) in individual mouse brains. These mini-pooled <em>in vivo</em> experiments generated primary midline gliomas with decreased tumor latency (median time to tumor formation of 3.6 weeks, <em>P</em> &lt; 0.0001, log-rank test compared to single-plex gRNA). Quantification of gRNA barcodes and CRISPR editing events revealed that all tumors contained cells with various disruptions of all target genes and suggested a multiclonal origin for the tumors as well as stronger selection for <em>Trp53</em> disruption compared to disruption of the other genes. This mouse modeling approach will streamline midline glioma research and enable complex experiments to understand tumor evolution and therapeutics.</div></div>","PeriodicalId":18917,"journal":{"name":"Neoplasia","volume":"62 ","pages":"Article 101139"},"PeriodicalIF":4.8,"publicationDate":"2025-03-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143562463","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Expression, regulation, function and clinical significance of B7-H6 on neutrophils in human gastric cancer","authors":"Pan Wang ,&nbsp;Peng Zhu ,&nbsp;Zheng-yan Li ,&nbsp;Yong-liang Zhao ,&nbsp;Fang-yuan Mao ,&nbsp;Liu-sheng Peng ,&nbsp;Shou-lu Luo ,&nbsp;Ping Luo ,&nbsp;Yu-gang Liu ,&nbsp;Mao Chen ,&nbsp;Yuan Zhuang","doi":"10.1016/j.neo.2025.101149","DOIUrl":"10.1016/j.neo.2025.101149","url":null,"abstract":"<div><div>Neutrophils are conspicuous components of gastric cancer (GC) tumors, increasing with tumor progression and poor patient survival. However, the phenotype, regulation, function and clinical relevance of neutrophils in human GC are presently unknown. We used flow cytometry analyses to examine levels and phenotype of neutrophils in samples from 50 patients with GC. Kaplan-Meier plots for patient survival were performed using the log-rank test, and multivariate analysis of prognostic factors for patient survival was performed using the Cox proportional hazards model. Neutrophils were isolated, stimulated and/or cultured for regulation and function assays. We found that GC patients showed a significantly higher neutrophil infiltration in tumors, and that neutrophil infiltration was positively associated with tumor progression but negatively correlated with patient survival. Most tumor-infiltrating neutrophils showed an activated CD54⁺ phenotype and expressed high level B7-H6. Tumor tissue culture supernatants from GC patients inhibited neutrophil apoptosis and induced the expression of CD54 and B7-H6 on neutrophils in time-dependent and dose-dependent manners. Intratumoral CD54⁺ neutrophils and B7-H6⁺ neutrophils positively correlated with increased G-CSF detection <em>ex vivo</em>; and <em>in vitro</em> both G-CSF and tumor-derived G-CSF induced the expression of CD54 and B7-H6 on neutrophils via NF-κB signaling pathway activation. Furthermore, blockade of B7-H6 promoted the apoptosis of tumor-infiltrating and tumor-conditioned neutrophils, and shortened their lifespan. Importantly, intratumoral B7-H6⁺ neutrophils increased with tumor progression and predicted poor patient survival. Our results illuminate a novel mechanism of B7-H6 expression on tumor-activated neutrophils in GC, and also suggest B7-H6⁺ neutrophils would be novel potential biomarkers in GC.</div></div>","PeriodicalId":18917,"journal":{"name":"Neoplasia","volume":"62 ","pages":"Article 101149"},"PeriodicalIF":4.8,"publicationDate":"2025-03-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143562536","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}