Pub Date : 2025-03-16DOI: 10.1016/j.neo.2025.101152
Sohum Patel , Eleanor Jenkins , Rutuj P Kusurkar , Sherry Lee , Wei Jiang , Avinoam Nevler , Matthew McCoy , Michael J Pishvaian , Rosalie C Sears , Jonathan R Brody , Charles J Yeo , Aditi Jain
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 in vitro and in vivo, 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.
{"title":"Targeting BARD1 suppresses a Myc-dependent transcriptional program and tumor growth in pancreatic ductal adenocarcinoma","authors":"Sohum Patel , Eleanor Jenkins , Rutuj P Kusurkar , Sherry Lee , Wei Jiang , Avinoam Nevler , Matthew McCoy , Michael J Pishvaian , Rosalie C Sears , Jonathan R Brody , Charles J Yeo , 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}
Pub Date : 2025-03-15DOI: 10.1016/j.neo.2025.101156
Caineng Cao , Le Wang , Feng Jiang , Qifeng Jin , Ting Jin , Shuang Huang , Qiaoying Hu , Yuanyuan Chen , Yongfeng Piao , Yonghong Hua , Xinglai Feng , Yi Zhou , Xiaozhong Chen
Background
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.
Methods
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).
Results
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 (p = 1.9615E-10) and IL-18 (p = 6.8467E-8) were increased after GM-CSF, while the proportion of CD19 (p = 0.000015), the concentrations of IgG (p = 0.000015) and CXCL12 (p = 0.000257) were decreased.
Conclusions
The combination of hypofractionated IMRT, temozolomide and GM-CSF for GBM was feasible and safe.
Trial Registration
ClinicalTrials.gov Identifier: NCT02663440.
{"title":"Granulocyte-macrophage colony-stimulating factor for newly diagnosed glioblastoma","authors":"Caineng Cao , Le Wang , Feng Jiang , Qifeng Jin , Ting Jin , Shuang Huang , Qiaoying Hu , Yuanyuan Chen , Yongfeng Piao , Yonghong Hua , Xinglai Feng , Yi Zhou , 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}
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 JAK2V617F and protease-activated receptor 1 (PAR1) by examining PAR1 expression and activation across various hematopoietic stem/progenitor cell (HSPC) subgroups, assessing their contribution to the hypercoagulable state in Ph-MPNs.
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 (n = 18), cord blood (CB) samples (n = 5) and healthy volunteers (n = 11). Specific subpopulations were sorted and analyzed for PAR1 expression and JAK2V617F status using qRT-PCR. PAR1 expression changes, along with other PAR pathway-related genes, were assessed post-treatment.
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 (p = 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 PAR1 expression (p < 0.0001), and several PAR-pathway-related genes were notably downregulated after treatment.
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.
{"title":"Targeting PAR1 activation in JAK2V617F-driven philadelphia-negative myeloproliferative neoplasms: Unraveling its role in thrombosis and disease progression","authors":"İldeniz USLU-BIÇAK , Meliha NALÇACI , 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<sup>-</sup>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<sup>-</sup>MPNs.</div><div>We investigated the effects of thrombin, a PAR1 antagonist (vorapaxar), and a JAK2 inhibitor (ruxolitinib) on Ph<sup>-</sup>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<sup>+</sup> cells (∼95 %) co-expressed CD34<sup>+</sup>, with a smaller JAK2V617F<sup>+</sup> PAR1<sup>+</sup> 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> < 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<sup>-</sup>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<sup>-</sup>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}
Pub Date : 2025-03-14DOI: 10.1016/j.neo.2025.101151
Anbarasu Kumaraswamy , Rahul Mannan , Olivia A. Swaim , Eva Rodansky , Xiao-Ming Wang , Aaron Udager , Rohit Mehra , Hui Li , Colm Morrissey , Eva Corey , Michael C. Haffner , Peter S. Nelson , Arul M. Chinnaiyan , Joel A. Yates , Joshi J. Alumkal
Background
Lysine-specific demethylase 1 (LSD1) is a histone demethylase and regulator of differentiation, including in cancer. A neuronal-specific isoform of LSD1—LSD1+8a—has been shown to play a key role in promoting neuronal differentiation in the developing brain. We previously determined that LSD1+8a 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.
Methods
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 in situ hybridization (RNA-ISH), and protein detection methods. We then validated our findings using an independent cohort of patient tumor samples.
Results
LSD1+8a 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 LSD1+8a 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 LSD1+8a mRNA in NEPC tumors vs. normal neuronal tissues.
Conclusions
Measuring LSD1+8a mRNA is a sensitive and specific method for the diagnosis of NEPC, which is often challenging.
{"title":"LSD1+8a is an RNA biomarker of neuroendocrine prostate cancer","authors":"Anbarasu Kumaraswamy , Rahul Mannan , Olivia A. Swaim , Eva Rodansky , Xiao-Ming Wang , Aaron Udager , Rohit Mehra , Hui Li , Colm Morrissey , Eva Corey , Michael C. Haffner , Peter S. Nelson , Arul M. Chinnaiyan , Joel A. Yates , 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}
Pub Date : 2025-03-12DOI: 10.1016/j.neo.2025.101142
Huai Liu , Yingzhou Fu , Ling Tang , Bo Song , Wangning Gu , Hongmin Yang , Tengfei Xiao , Hui Wang , Pan Chen
Background
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.
Methods
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 in vivo.
Results
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.
Conclusion
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.
{"title":"O-GlcNAc-modified HOXA9 suppresses ferroptosis via promoting UBR5-mediated SIRT6 degradation in nasopharyngeal carcinoma","authors":"Huai Liu , Yingzhou Fu , Ling Tang , Bo Song , Wangning Gu , Hongmin Yang , Tengfei Xiao , Hui Wang , 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, Fe<sup>2+</sup> 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, Fe<sup>2+</sup> 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}
Pub Date : 2025-03-08DOI: 10.1016/j.neo.2025.101150
Qian Li , Ziyi Peng , Li Lin , Zhiying Zhang , Jing Ma , Lin Chen , Su Liu , Shuang Gao , Linchuang Jia , Jingjing Wang , Zeng Cao , Xingli Zhao , Zhiqiang Liu , Yafei Wang
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.
{"title":"HRP2 regulating MICU1-mediated Ca2+ overload to dictate chemoresistance of multiple myeloma","authors":"Qian Li , Ziyi Peng , Li Lin , Zhiying Zhang , Jing Ma , Lin Chen , Su Liu , Shuang Gao , Linchuang Jia , Jingjing Wang , Zeng Cao , Xingli Zhao , Zhiqiang Liu , 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 (Ca<sup>2+</sup>) 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<sup>+</sup>CD19<sup>+</sup> 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}
Pub Date : 2025-03-07DOI: 10.1016/j.neo.2025.101139
Sophie R. Wu , Julianne Sharpe , Joshua Tolliver , Abigail J. Groth , Reid Chen , María E. Guerra García , Vennesa Valentine , Nerissa T. Williams , Sheeba Jacob , Zachary J. Reitman
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 Trp53, 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 Trp53 disruption using next-generation sequencing (NGS) and immunohistochemistry (IHC). Next, we disrupted multiple midline glioma tumor suppressor genes (Trp53, Pten, Atm, Cdkn2a) in individual mouse brains. These mini-pooled in vivo experiments generated primary midline gliomas with decreased tumor latency (median time to tumor formation of 3.6 weeks, P < 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 Trp53 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.
{"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 , Julianne Sharpe , Joshua Tolliver , Abigail J. Groth , Reid Chen , María E. Guerra García , Vennesa Valentine , Nerissa T. Williams , Sheeba Jacob , 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> < 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}
Pub Date : 2025-03-06DOI: 10.1016/j.neo.2025.101149
Pan Wang , Peng Zhu , Zheng-yan Li , Yong-liang Zhao , Fang-yuan Mao , Liu-sheng Peng , Shou-lu Luo , Ping Luo , Yu-gang Liu , Mao Chen , Yuan Zhuang
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 ex vivo; and in vitro 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.
{"title":"Expression, regulation, function and clinical significance of B7-H6 on neutrophils in human gastric cancer","authors":"Pan Wang , Peng Zhu , Zheng-yan Li , Yong-liang Zhao , Fang-yuan Mao , Liu-sheng Peng , Shou-lu Luo , Ping Luo , Yu-gang Liu , Mao Chen , 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<sup>+</sup> 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<sup>+</sup> neutrophils and B7-H6<sup>+</sup> 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<sup>+</sup> 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<sup>+</sup> 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}
Pub Date : 2025-03-03DOI: 10.1016/j.neo.2025.101147
John S. Wang , Samuel J. Schellenberg , Athena Demeros , Adam Y. Lin
Exosomes are extracellular vehicles that facilitate intra-cellular communication via transport of critical proteins and genetic material. Every exosome is intrinsically reflective of the cell from which it was derived and can even mimic effector functions of their parent cells. In recent years, with the success of CAR-T therapies, there has been growing interest in characterizing exosomes derived from CAR-T cells. CAR exosomes contain the same cytotoxic granules as their parent cells and have demonstrated significant anti-tumor activity in vitro and in animal models. Moreover, infusion of CAR exosomes in animal models did not generate cytokine release syndrome. Conversely, there are also novel bispecific antibodies which target tumor-derived exosomes in hopes of derailing immunosuppressive pathways mediated by exosomes produced from malignant cells. The two most promising examples include (a) BsE CD73 x EpCAM which binds and inhibits exosomal CD73 to suppress production of immunosuppressant adenosine and (b) BsE CD3 x PD-L1 which targets exosomal PD-L1 within the tumor microenvironment to guide cytotoxic T-cells towards tumor cells. As our understanding of exosome biology continues to evolve, opportunities for advances in cellular therapies will grow in tandem.
{"title":"Exosomes in review: A new frontier in CAR-T cell therapies","authors":"John S. Wang , Samuel J. Schellenberg , Athena Demeros , Adam Y. Lin","doi":"10.1016/j.neo.2025.101147","DOIUrl":"10.1016/j.neo.2025.101147","url":null,"abstract":"<div><div>Exosomes are extracellular vehicles that facilitate intra-cellular communication via transport of critical proteins and genetic material. Every exosome is intrinsically reflective of the cell from which it was derived and can even mimic effector functions of their parent cells. In recent years, with the success of CAR-T therapies, there has been growing interest in characterizing exosomes derived from CAR-T cells. CAR exosomes contain the same cytotoxic granules as their parent cells and have demonstrated significant anti-tumor activity <em>in vitro</em> and in animal models. Moreover, infusion of CAR exosomes in animal models did not generate cytokine release syndrome. Conversely, there are also novel bispecific antibodies which target tumor-derived exosomes in hopes of derailing immunosuppressive pathways mediated by exosomes produced from malignant cells. The two most promising examples include (a) BsE CD73 x EpCAM which binds and inhibits exosomal CD73 to suppress production of immunosuppressant adenosine and (b) BsE CD3 x PD-L1 which targets exosomal PD-L1 within the tumor microenvironment to guide cytotoxic T-cells towards tumor cells. As our understanding of exosome biology continues to evolve, opportunities for advances in cellular therapies will grow in tandem.</div></div>","PeriodicalId":18917,"journal":{"name":"Neoplasia","volume":"62 ","pages":"Article 101147"},"PeriodicalIF":4.8,"publicationDate":"2025-03-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143529740","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}
Pub Date : 2025-02-25DOI: 10.1016/j.neo.2025.101140
Jing Chen , Shenghua Zhang , Xinmei Huang , Qianqian Wang , Weiyan Xu , Jing Huang , Yuming Su , Qinkun Sun , Xiaojuan Du , Baocai Xing , Xiaoyan Qiu
Background
Liver metastasis is a leading cause of colorectal cancer mortality. Therefore, the underlying mechanism and potential therapeutic target of colorectal cancer liver metastasis urge to be found. Mounting evidence indicates that cancer-derived sialylated IgG promotes tumor formation and progression. However, the role of sialylated IgG in colorectal cancer liver metastasis remains undefined.
Materials and methods
Analysis of sialylated IgG in paired tumor tissues and adjacent normal tissues from 65 colorectal cancer patients was performed using immunohistochemical staining. Functional assays of sialylated IgG were explored in vitro and in vivo. The downstream target of sialylated IgG was investigated by performing gene-set enrichment analysis, ubiquitination assay, cycloheximide chase assay, acetylation assay and co-immunoprecipitation.
Results
Here, our investigation reveals that sialylated IgG is significantly upregulated in colorectal cancer and that the increase of IgG is positively associated with liver metastasis and poor overall survival in colorectal cancer patients. Sialylated IgG promotes colorectal cancer cell migration, invasion and liver metastasis. Notably, anti-sialylated IgG antibody effectively blocks colorectal cancer liver metastasis in mouse models. Mechanistically, sialylated IgG upregulates c-Myc protein level by decreasing c-Myc ubiquitination. Moreover, we find that p300/CBP can stabilize c-Myc by reducing c-Myc ubiquitination. Overexpression of p300/CBP protects c-Myc protein level from sialylated IgG-knockdown in a lysine acetyltransferase activity-dependent manner. Furthermore, sialylated IgG upregulates p300 protein level through integrin β4-FAK-Src-Erk signaling.
Conclusion
Collectively, these results indicate that a novel sialylated IgG-integrin β4-FAK-Src-Erk-p300-c-Myc signaling pathway promotes colorectal cancer liver metastasis, thus providing potential therapeutic targets for colorectal cancer liver metastasis.
{"title":"Sialylated IgG-activated integrin β4-Src-Erk axis stabilizes c-Myc in a p300 lysine acetyltransferase-dependent manner to promote colorectal cancer liver metastasis","authors":"Jing Chen , Shenghua Zhang , Xinmei Huang , Qianqian Wang , Weiyan Xu , Jing Huang , Yuming Su , Qinkun Sun , Xiaojuan Du , Baocai Xing , Xiaoyan Qiu","doi":"10.1016/j.neo.2025.101140","DOIUrl":"10.1016/j.neo.2025.101140","url":null,"abstract":"<div><h3>Background</h3><div>Liver metastasis is a leading cause of colorectal cancer mortality. Therefore, the underlying mechanism and potential therapeutic target of colorectal cancer liver metastasis urge to be found. Mounting evidence indicates that cancer-derived sialylated IgG promotes tumor formation and progression. However, the role of sialylated IgG in colorectal cancer liver metastasis remains undefined.</div></div><div><h3>Materials and methods</h3><div>Analysis of sialylated IgG in paired tumor tissues and adjacent normal tissues from 65 colorectal cancer patients was performed using immunohistochemical staining. Functional assays of sialylated IgG were explored in vitro and in vivo. The downstream target of sialylated IgG was investigated by performing gene-set enrichment analysis, ubiquitination assay, cycloheximide chase assay, acetylation assay and co-immunoprecipitation.</div></div><div><h3>Results</h3><div>Here, our investigation reveals that sialylated IgG is significantly upregulated in colorectal cancer and that the increase of IgG is positively associated with liver metastasis and poor overall survival in colorectal cancer patients. Sialylated IgG promotes colorectal cancer cell migration, invasion and liver metastasis. Notably, anti-sialylated IgG antibody effectively blocks colorectal cancer liver metastasis in mouse models. Mechanistically, sialylated IgG upregulates c-Myc protein level by decreasing c-Myc ubiquitination. Moreover, we find that p300/CBP can stabilize c-Myc by reducing c-Myc ubiquitination. Overexpression of p300/CBP protects c-Myc protein level from sialylated IgG-knockdown in a lysine acetyltransferase activity-dependent manner. Furthermore, sialylated IgG upregulates p300 protein level through integrin β4-FAK-Src-Erk signaling.</div></div><div><h3>Conclusion</h3><div>Collectively, these results indicate that a novel sialylated IgG-integrin β4-FAK-Src-Erk-p300-c-Myc signaling pathway promotes colorectal cancer liver metastasis, thus providing potential therapeutic targets for colorectal cancer liver metastasis.</div></div>","PeriodicalId":18917,"journal":{"name":"Neoplasia","volume":"61 ","pages":"Article 101140"},"PeriodicalIF":4.8,"publicationDate":"2025-02-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143480009","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}
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