Pub Date : 2025-06-20DOI: 10.1016/j.neo.2025.101201
Kostas A. Papavassiliou , Alice G. Vassiliou , Athanasios G. Papavassiliou
Inactivation of p53 due to mutation is observed in approximately half of all human cancer cases, therefore, restoration of the tumor suppressor function of oncogenic p53 mutants represents an attractive and rational therapeutic approach. Currently, multiple mutant p53 reactivators have been developed, but only a handful have entered clinical trials [1]. PC14586 (rezatapopt) is an orally available small-molecule reactivator of the Y220C-mutant p53 protein that showed preliminary efficacy and a favorable safety profile in a phase I clinical trial [2] and is now undergoing evaluation in a phase II clinical trial in patients with advanced solid tumors harboring the TP53Y220C mutation (NCT04585750). Although rezatapopt and other p53 mutant reactivators are under clinical assessment, there are still many knowledge gaps that need to be filled to unleash their full therapeutic potential.
The preclinical data presented in a recently published research article by Puzio-Kuter et al. achieve to enhance our understanding of the mechanisms and effects of p53-Y220C reactivator compounds and underscore the potential of targeting p53 mutants in cancer therapy [3]. Through this spotlight article, we aim to summarize the findings and emphasize the clinical implications of the study by Puzio-Kutler et al.
{"title":"Rezatapopt: A promising small-molecule “refolder” specific for TP53Y220C mutant tumors","authors":"Kostas A. Papavassiliou , Alice G. Vassiliou , Athanasios G. Papavassiliou","doi":"10.1016/j.neo.2025.101201","DOIUrl":"10.1016/j.neo.2025.101201","url":null,"abstract":"<div><div>Inactivation of p53 due to mutation is observed in approximately half of all human cancer cases, therefore, restoration of the tumor suppressor function of oncogenic p53 mutants represents an attractive and rational therapeutic approach. Currently, multiple mutant p53 reactivators have been developed, but only a handful have entered clinical trials [<span><span>1</span></span>]. PC14586 (rezatapopt) is an orally available small-molecule reactivator of the Y220C-mutant p53 protein that showed preliminary efficacy and a favorable safety profile in a phase I clinical trial [<span><span>2</span></span>] and is now undergoing evaluation in a phase II clinical trial in patients with advanced solid tumors harboring the <em>TP53</em><sup>Y220C</sup> mutation (NCT04585750). Although rezatapopt and other p53 mutant reactivators are under clinical assessment, there are still many knowledge gaps that need to be filled to unleash their full therapeutic potential.</div><div>The preclinical data presented in a recently published research article by Puzio-Kuter et al. achieve to enhance our understanding of the mechanisms and effects of p53-Y220C reactivator compounds and underscore the potential of targeting p53 mutants in cancer therapy [<span><span>3</span></span>]. Through this spotlight article, we aim to summarize the findings and emphasize the clinical implications of the study by Puzio-Kutler et al.</div></div>","PeriodicalId":18917,"journal":{"name":"Neoplasia","volume":"67 ","pages":"Article 101201"},"PeriodicalIF":4.8,"publicationDate":"2025-06-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144321683","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-06-18DOI: 10.1016/j.neo.2025.101197
Natalia Gorbokon , Seyma Büyücek , Henning Plage , Neele Heckmann , Ronald Simon , Maximilian Lennartz , Martina Kluth , Katharina Teljuk , Claudia Hube-Magg , Sarah Minner , Eike Burandt , Till S. Clauditz , Waldemar Wilczak , Guido Sauter , David Dum , Andrea Hinsch , Hans Heinzer , Alexander Haese , Thorsten Schlomm , Andreas M Luebke , Sarah Weinberger
Loss of S-methyl-5′-thioadenosine phosphorylase (MTAP) expression offers a therapeutic option through synthetic lethality and confers resistance to immune checkpoint inhibitors in various cancers. To assess MTAP prevalence in prostate cancer, a tissue microarray of 17,747 samples was analyzed via immunohistochemistry. Normal prostate glands showed weak to moderate cytoplasmic MTAP staining. In 13,189 interpretable cancers, a complete loss of MTAP staining was seen in 33 (0.3 %) tumors, while MTAP staining was considered 1+ in 14.8 %, 2+ in 42.2 %, and 3+ in 42.7 % of tumors. Fluorescence in situ hybridization analysis of 9 MTAP-negative cancers confirmed homozygous MTAP deletion in all of these tumors. MTAP staining was significantly stronger in cancers harboring the TMPRSS2:ERG fusion than in ERG fusion negative tumors (p < 0.0001). A comparison with clinico-pathological features revealed inverse correlations depending on the ERG fusion status: In ERG-negative cancers, high (3+) MTAP expression correlated with advanced pT stage, high Gleason grade, and early PSA recurrence (p < 0.0001 each). Conversely, in ERG-positive tumors, MTAP expression decreased with advanced pT stage (p < 0.0001), high classical (p = 0.0004) and quantitative Gleason grade (p = 0.0005), and low (1+) MTAP expression was significantly linked to early PSA recurrence (p = 0.0012). Comparison with 11 previously analyzed chromosomal deletions identified ERG-status-dependent positive or negative associations between MTAP expression and deletions of PTEN and 12p13 (p ≤ 0.0274), suggesting functional interactions. Taken together, the results of our study demonstrate that MTAP deficiency is exceedingly rare in prostate cancer, while high MTAP expression is a strong and independent marker for poor prognosis in ERG negative cancers.
{"title":"Prognostic role of high MTAP expression is reversed by the ERG status in prostate cancer treated by radical prostatectomy","authors":"Natalia Gorbokon , Seyma Büyücek , Henning Plage , Neele Heckmann , Ronald Simon , Maximilian Lennartz , Martina Kluth , Katharina Teljuk , Claudia Hube-Magg , Sarah Minner , Eike Burandt , Till S. Clauditz , Waldemar Wilczak , Guido Sauter , David Dum , Andrea Hinsch , Hans Heinzer , Alexander Haese , Thorsten Schlomm , Andreas M Luebke , Sarah Weinberger","doi":"10.1016/j.neo.2025.101197","DOIUrl":"10.1016/j.neo.2025.101197","url":null,"abstract":"<div><div>Loss of S-methyl-5′-thioadenosine phosphorylase (MTAP) expression offers a therapeutic option through synthetic lethality and confers resistance to immune checkpoint inhibitors in various cancers. To assess MTAP prevalence in prostate cancer, a tissue microarray of 17,747 samples was analyzed via immunohistochemistry. Normal prostate glands showed weak to moderate cytoplasmic MTAP staining. In 13,189 interpretable cancers, a complete loss of MTAP staining was seen in 33 (0.3 %) tumors, while MTAP staining was considered 1+ in 14.8 %, 2+ in 42.2 %, and 3+ in 42.7 % of tumors. Fluorescence in situ hybridization analysis of 9 MTAP-negative cancers confirmed homozygous MTAP deletion in all of these tumors. MTAP staining was significantly stronger in cancers harboring the <em>TMPRSS2:ERG</em> fusion than in ERG fusion negative tumors (<em>p</em> < 0.0001). A comparison with clinico-pathological features revealed inverse correlations depending on the ERG fusion status: In ERG-negative cancers, high (3+) MTAP expression correlated with advanced pT stage, high Gleason grade, and early PSA recurrence (<em>p</em> < 0.0001 each). Conversely, in ERG-positive tumors, MTAP expression decreased with advanced pT stage (<em>p</em> < 0.0001), high classical (<em>p</em> = 0.0004) and quantitative Gleason grade (<em>p</em> = 0.0005), and low (1+) MTAP expression was significantly linked to early PSA recurrence (<em>p</em> = 0.0012). Comparison with 11 previously analyzed chromosomal deletions identified ERG-status-dependent positive or negative associations between MTAP expression and deletions of PTEN and 12p13 (<em>p</em> ≤ 0.0274), suggesting functional interactions. Taken together, the results of our study demonstrate that MTAP deficiency is exceedingly rare in prostate cancer, while high MTAP expression is a strong and independent marker for poor prognosis in ERG negative cancers.</div></div>","PeriodicalId":18917,"journal":{"name":"Neoplasia","volume":"67 ","pages":"Article 101197"},"PeriodicalIF":4.8,"publicationDate":"2025-06-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144306250","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}
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 VEGFR2R1032Q alone or in combination with VEGFR2WT, we showed that the effects of mutated VEGFR2 are at least in part due to the ability of VEGFR2R1032Q to form functional heterodimers with co-expressed VEGFR2WT 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.
{"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 , Michela Corsini , Roberto Bresciani , Angela M. Rizzo , Luca Zammataro , Paola A. Corsetto , Elisabetta Grillo , 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<sup>R1032Q</sup> alone or in combination with VEGFR2<sup>WT</sup>, we showed that the effects of mutated VEGFR2 are at least in part due to the ability of VEGFR2<sup>R1032Q</sup> to form functional heterodimers with co-expressed VEGFR2<sup>WT</sup> 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":"2025-06-14","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}
Pub Date : 2025-06-13DOI: 10.1016/j.neo.2025.101185
Walter V. Velasco , Maria T. Grimaldo , Nastaran Karimi , Michael J. Clowers , Avantika Krishna , Ranran Wu , Rahmah Ejaz , Bo Yuan , Segundo del Aguila , Iman Bouchelkia , Javier Eduardo Moreno Barragan , Katherine E. Larsen , Yasmina Rezai , Farbod Khalaj , Kyler Mitra , Carlos Reyna Rodriguez , Ricardo Millares , Angelica Baca de Anda , Susana Castro-Pando , Umesh C. Karandikar , Seyed Javad Moghaddam
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 Pseudomonadotas, while gut Bacillota, particularly Turicibacter, and Ileibacterium 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.
{"title":"Comparative effects of combustible cigarette versus electronic cigarette exposures on KRAS mutant lung cancer promotion","authors":"Walter V. Velasco , Maria T. Grimaldo , Nastaran Karimi , Michael J. Clowers , Avantika Krishna , Ranran Wu , Rahmah Ejaz , Bo Yuan , Segundo del Aguila , Iman Bouchelkia , Javier Eduardo Moreno Barragan , Katherine E. Larsen , Yasmina Rezai , Farbod Khalaj , Kyler Mitra , Carlos Reyna Rodriguez , Ricardo Millares , Angelica Baca de Anda , Susana Castro-Pando , Umesh C. Karandikar , 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":"2025-06-13","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}
Pub Date : 2025-06-11DOI: 10.1016/j.neo.2025.101194
Yiming Liu , Xingyu Jiang , Dongquan Jing , Yanting Lin , Rui Gao , Qixiang Zhao , Huijuan Da , Yiming Ren , Qiuhua Cao , Ning Liu , Xiaoyun Han , Juan Du , Xinghua Gao
Background: Long-chain acyl-CoA synthetase 4 (ACSL4), a crucial modulator of ferroptosis, is associated with tumor progression, though its impact on colorectal cancer (CRC) immune dynamics is not fully understood.
Methods: ACSL4 expression was analyzed in CRC tissues and correlated with patient prognosis. Effects of ACSL4 were evaluated in CRC cells in vitro and in subcutaneous and orthotopic CRC models. Flow cytometry and immunofluorescence were used to evaluate immune cell infiltration. RNA sequencing and RT-PCR were employed to identify ACSL4-regulated signaling pathways. The effect of ACSL4 silencing on PD-L1 blockade efficacy was also examined.
Results: ACSL4 levels were markedly increased in CRC and linked to unfavorable patient outcomes. While ACSL4 knockdown had no direct effect on CRC cell proliferation, it significantly suppressed tumor growth in immunocompetent mice. ACSL4 depletion enhanced CD3⁺ and CD8⁺ T cell infiltration and upregulated chemokines (CXCL10, CXCL11) and antigen presentation genes (H2k1, TAP1, TAPBP). Transcriptomic analysis highlighted activation of the RIG-I-MAVS-driven type I interferon pathway. Co-culture assays demonstrated that ACSL4 knockdown promoted CD8⁺ T cell activation, and ACSL4-deficient tumors exhibited enhanced responsiveness to PD-L1 blockade.
Conclusions: ACSL4 suppresses anti-tumor immunity in CRC by modulating the RIG-I-MAVS-IFN pathway, highlighting ACSL4 as a promising target for CRC immunotherapy.
{"title":"ACSL4 knockdown inhibits colorectal cancer progression through stimulating anti-tumor immunity","authors":"Yiming Liu , Xingyu Jiang , Dongquan Jing , Yanting Lin , Rui Gao , Qixiang Zhao , Huijuan Da , Yiming Ren , Qiuhua Cao , Ning Liu , Xiaoyun Han , Juan Du , Xinghua Gao","doi":"10.1016/j.neo.2025.101194","DOIUrl":"10.1016/j.neo.2025.101194","url":null,"abstract":"<div><div>Background: Long-chain acyl-CoA synthetase 4 (ACSL4), a crucial modulator of ferroptosis, is associated with tumor progression, though its impact on <strong>colorectal cancer (</strong>CRC) immune dynamics is not fully understood.</div><div>Methods: ACSL4 expression was analyzed in CRC tissues and correlated with patient prognosis. Effects of ACSL4 were evaluated in CRC cells in vitro and in subcutaneous and orthotopic CRC models. Flow cytometry and immunofluorescence were used to evaluate immune cell infiltration. RNA sequencing and RT-PCR were employed to identify ACSL4-regulated signaling pathways. The effect of ACSL4 silencing on PD-L1 blockade efficacy was also examined.</div><div>Results: ACSL4 levels were markedly increased in CRC and linked to unfavorable patient outcomes. While <em>ACSL4</em> knockdown had no direct effect on CRC cell proliferation, it significantly suppressed tumor growth in immunocompetent mice. ACSL4 depletion enhanced CD3⁺ and CD8⁺ T cell infiltration and upregulated chemokines (CXCL10, CXCL11) and antigen presentation genes (H2k1, TAP1, TAPBP). Transcriptomic analysis highlighted activation of the RIG-I-MAVS-driven type I interferon pathway. Co-culture assays demonstrated that <em>ACSL4</em> knockdown promoted CD8⁺ T cell activation, and ACSL4-deficient tumors exhibited enhanced responsiveness to PD-L1 blockade.</div><div>Conclusions: ACSL4 suppresses anti-tumor immunity in CRC by modulating the RIG-I-MAVS-IFN pathway, highlighting ACSL4 as a promising target for CRC immunotherapy.</div></div>","PeriodicalId":18917,"journal":{"name":"Neoplasia","volume":"67 ","pages":"Article 101194"},"PeriodicalIF":4.8,"publicationDate":"2025-06-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144253315","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-06-10DOI: 10.1016/j.neo.2025.101191
Yan Guo , Hongyang Yu , Jinyang Li , Kewei Liu , Mengyi Han , Yuxin Tang , Li Su , Xianfeng Li , Haixia Wu , Dongfeng Chen
{"title":"Corrigendum to “DNA-methylation eraser TET2 activates WTIP expression to suppress an AKT-dependent chemoresistance of gastric cancer” [Neoplasia volume 2025 Apr 24:65:101166]","authors":"Yan Guo , Hongyang Yu , Jinyang Li , Kewei Liu , Mengyi Han , Yuxin Tang , Li Su , Xianfeng Li , Haixia Wu , Dongfeng Chen","doi":"10.1016/j.neo.2025.101191","DOIUrl":"10.1016/j.neo.2025.101191","url":null,"abstract":"","PeriodicalId":18917,"journal":{"name":"Neoplasia","volume":"66 ","pages":"Article 101191"},"PeriodicalIF":4.8,"publicationDate":"2025-06-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144254285","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-06-09DOI: 10.1016/j.neo.2025.101190
Kassidy M. Jungles , Caroline R. Bishop , Cydnee M. Wilson , Meilan Liu , Kalli R. Jungles , Kari Wilder-Romans , Corey W. Speers , Lori J. Pierce , James M. Rae
Triple negative breast cancer (TNBC) is an aggressive breast cancer subtype that disproportionately impacts Black women and has limited effective therapeutic options. Consequently, there is an urgent need to develop novel approaches for the treatment of TNBC. Previously, we identified monopolar spindle kinase I (Mps1 or TTK), which is upregulated in TNBC patients after radiotherapy, as a potential therapeutic target. We found that TTK inhibition sensitizes human TNBC to radiotherapy (RT) both in vitro and in vivo; however, these studies were performed in immunodeficient models. Here, we extended those studies into syngeneic murine models of TNBC using two TTK inhibitors: empesertib and the novel TTK inhibitor CFI-402257 (also known as luvixasertib) that was recently granted FDA fast track approval in breast cancer. These studies demonstrate that TTK inhibition radiosensitizes syngeneic murine models of TNBC and increases the production of micronuclei and aneuploidy. Mechanistic studies demonstrate that TTK inhibition and RT alter the tumor immune microenvironment of TNBC by modifying the production of antitumoral type I interferon (T1IFN). In vivo, TTK inhibition sensitizes syngeneic models of TNBC to RT. Furthermore, combining TTK inhibition and RT also potentiates T1IFN signaling, suggesting that combination treatment may induce antitumoral immunity in immunocompetent models. Taken together, these studies demonstrate that TTK inhibition enhances radiosensitivity and TTK inhibition with RT modulates the immune landscape of TNBC. Collectively, this combination may represent a novel therapeutic strategy to improve outcomes for patients with TNBC by both direct tumor cytotoxicity and by promoting an immune-responsive environment.
{"title":"Targeting monopolar spindle kinase I (Mps1 or TTK) induces radiosensitization in syngeneic models of triple negative breast cancer (TNBC) and potentiates type I interferon (T1IFN) signaling","authors":"Kassidy M. Jungles , Caroline R. Bishop , Cydnee M. Wilson , Meilan Liu , Kalli R. Jungles , Kari Wilder-Romans , Corey W. Speers , Lori J. Pierce , James M. Rae","doi":"10.1016/j.neo.2025.101190","DOIUrl":"10.1016/j.neo.2025.101190","url":null,"abstract":"<div><div>Triple negative breast cancer (TNBC) is an aggressive breast cancer subtype that disproportionately impacts Black women and has limited effective therapeutic options. Consequently, there is an urgent need to develop novel approaches for the treatment of TNBC. Previously, we identified monopolar spindle kinase I (Mps1 or TTK), which is upregulated in TNBC patients after radiotherapy, as a potential therapeutic target. We found that TTK inhibition sensitizes human TNBC to radiotherapy (RT) both <em>in vitro</em> and <em>in vivo</em>; however, these studies were performed in immunodeficient models. Here, we extended those studies into syngeneic murine models of TNBC using two TTK inhibitors: empesertib and the novel TTK inhibitor CFI-402257 (also known as luvixasertib) that was recently granted FDA fast track approval in breast cancer. These studies demonstrate that TTK inhibition radiosensitizes syngeneic murine models of TNBC and increases the production of micronuclei and aneuploidy. Mechanistic studies demonstrate that TTK inhibition and RT alter the tumor immune microenvironment of TNBC by modifying the production of antitumoral type I interferon (T1IFN). <em>In vivo</em>, TTK inhibition sensitizes syngeneic models of TNBC to RT. Furthermore, combining TTK inhibition and RT also potentiates T1IFN signaling, suggesting that combination treatment may induce antitumoral immunity in immunocompetent models. Taken together, these studies demonstrate that TTK inhibition enhances radiosensitivity and TTK inhibition with RT modulates the immune landscape of TNBC. Collectively, this combination may represent a novel therapeutic strategy to improve outcomes for patients with TNBC by both direct tumor cytotoxicity and by promoting an immune-responsive environment.</div></div>","PeriodicalId":18917,"journal":{"name":"Neoplasia","volume":"66 ","pages":"Article 101190"},"PeriodicalIF":4.8,"publicationDate":"2025-06-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144241619","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-06-06DOI: 10.1016/j.neo.2025.101189
Mohamed Kamal , Stephanie N. Shishido , Jeremy Mason , Krina Patel , Elisabet E. Manasanch , Robert Z. Orlowski , Peter Kuhn
Multiple myeloma (MM) is an aggressive hematologic malignancy arising from plasma cell (PC) proliferation in the bone marrow, progressing from its precursor states MGUS and SMM. Despite therapeutic advances, MM remains incurable, underscoring the need for better risk stratification and early detection. Tumor heterogeneity and dynamic immune microenvironment changes drive progression, yet bulk analyses overlook rare subpopulations critical to disease evolution and resistance. This study employed multiplexed targeted proteomics to characterize bone marrow aspirates (BMA) from 22 patients to observe the change in the distribution of PCs and tumor immune microenvironment (TiME) cells across MM disease states and controls. Bone marrow samples were processed, stained with a 29-metal-labeled antibody panel, and analyzed using computational clustering approaches. Clustering of PCs revealed changes in subtypes with disease progression, marked by shifts from CD45-positive/CD138-low subpopulations in precursor states to CD45-negative/CD138-high populations in advanced MM. Analysis of the TiME identified distinct immune phenotypes, with significant reductions in monocyte/macrophage and lymphoid clusters across MM states compared to controls. Notably, a distinct PC cluster enriched in NDMM and RRMM exhibited high BCMA and CD138 expression, suggesting a potential role in disease progression. These findings provide critical insights into MM evolution and immune landscape alterations, with implications for targeted therapeutic strategies.
{"title":"Single-cell proteomic analysis reveals Multiple Myeloma heterogeneity and the dynamics of the tumor immune microenvironment in precursor and advanced states","authors":"Mohamed Kamal , Stephanie N. Shishido , Jeremy Mason , Krina Patel , Elisabet E. Manasanch , Robert Z. Orlowski , Peter Kuhn","doi":"10.1016/j.neo.2025.101189","DOIUrl":"10.1016/j.neo.2025.101189","url":null,"abstract":"<div><div>Multiple myeloma (MM) is an aggressive hematologic malignancy arising from plasma cell (PC) proliferation in the bone marrow, progressing from its precursor states MGUS and SMM. Despite therapeutic advances, MM remains incurable, underscoring the need for better risk stratification and early detection. Tumor heterogeneity and dynamic immune microenvironment changes drive progression, yet bulk analyses overlook rare subpopulations critical to disease evolution and resistance. This study employed multiplexed targeted proteomics to characterize bone marrow aspirates (BMA) from 22 patients to observe the change in the distribution of PCs and tumor immune microenvironment (TiME) cells across MM disease states and controls. Bone marrow samples were processed, stained with a 29-metal-labeled antibody panel, and analyzed using computational clustering approaches. Clustering of PCs revealed changes in subtypes with disease progression, marked by shifts from CD45-positive/CD138-low subpopulations in precursor states to CD45-negative/CD138-high populations in advanced MM. Analysis of the TiME identified distinct immune phenotypes, with significant reductions in monocyte/macrophage and lymphoid clusters across MM states compared to controls. Notably, a distinct PC cluster enriched in NDMM and RRMM exhibited high BCMA and CD138 expression, suggesting a potential role in disease progression. These findings provide critical insights into MM evolution and immune landscape alterations, with implications for targeted therapeutic strategies.</div></div>","PeriodicalId":18917,"journal":{"name":"Neoplasia","volume":"66 ","pages":"Article 101189"},"PeriodicalIF":4.8,"publicationDate":"2025-06-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144230855","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-06-04DOI: 10.1016/j.neo.2025.101192
Xiaoyue He , Xiaohong Xia , Ziying Lei , Mengfan Tang , Jiangyu Zhang , Yuning Liao , Hongbiao Huang
The overexpression and amplification of HER2 occurs in breast cancer. However, the mechanism of HER2 action in tumor has not yet been elucidated. HER2 can be degraded by the UPS system, and several HER2-associated E3s have been identified, but the DUB for HER2 has not yet been uncovered. Targeted therapy against HER2 has achieved impressive efficacy in patients with HER2-positive breast cancer. Herein, using MTS, Western blot, Co-IP, colony formation, RT‒qPCR, EdU, flow cytometry, immunofluorescence assays and xenograft model, we elucidated that USP7 deletion inhibited the growth of HER2-positive breast cancer cell by decreasing HER2 protein abundance. We found that USP7 was highly expressed in HER2-positive breast cancer and the expression of USP7 and HER2 was positively correlated. USP7 overexpression accelerated cell cycle progression. Mechanistically, USP7 interacted with HER2 and decreased HER2 ubiquitination to stabilize its expression. Moreover, USP7 knockdown inhibited tumor growth in vivo and in vitro. In addition, HER2 overexpression partially reversed cell growth inhibition induced by USP7 inhibition. Analyses of clinical samples revealed that USP7 overexpression was associated with poor prognosis in patients with HER2+ breast cancer. Thus, this study revealed that USP7, as a DUB of HER2, may be a potential therapeutic target for patient with HER2+ breast cancer.
{"title":"The deubiquitinase USP7 stabilizes HER2 expression and promotes breast cancer progression","authors":"Xiaoyue He , Xiaohong Xia , Ziying Lei , Mengfan Tang , Jiangyu Zhang , Yuning Liao , Hongbiao Huang","doi":"10.1016/j.neo.2025.101192","DOIUrl":"10.1016/j.neo.2025.101192","url":null,"abstract":"<div><div>The overexpression and amplification of HER2 occurs in breast cancer. However, the mechanism of HER2 action in tumor has not yet been elucidated. HER2 can be degraded by the UPS system, and several HER2-associated E3s have been identified, but the DUB for HER2 has not yet been uncovered. Targeted therapy against HER2 has achieved impressive efficacy in patients with HER2-positive breast cancer. Herein, using MTS, Western blot, Co-IP, colony formation, RT‒qPCR, EdU, flow cytometry, immunofluorescence assays and xenograft model, we elucidated that USP7 deletion inhibited the growth of HER2-positive breast cancer cell by decreasing HER2 protein abundance. We found that USP7 was highly expressed in HER2-positive breast cancer and the expression of USP7 and HER2 was positively correlated. USP7 overexpression accelerated cell cycle progression. Mechanistically, USP7 interacted with HER2 and decreased HER2 ubiquitination to stabilize its expression. Moreover, USP7 knockdown inhibited tumor growth in vivo and in vitro. In addition, HER2 overexpression partially reversed cell growth inhibition induced by USP7 inhibition. Analyses of clinical samples revealed that USP7 overexpression was associated with poor prognosis in patients with HER2+ breast cancer. Thus, this study revealed that USP7, as a DUB of HER2, may be a potential therapeutic target for patient with HER2+ breast cancer.</div></div>","PeriodicalId":18917,"journal":{"name":"Neoplasia","volume":"66 ","pages":"Article 101192"},"PeriodicalIF":4.8,"publicationDate":"2025-06-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144213154","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-06-04DOI: 10.1016/j.neo.2025.101188
Yuling Chi , Shireen Chikara , Eduardo Mere Del Aguila , Tuo Zhang , Jacob B. Geri , David M. Nanus , Lorraine J. Gudas
Clear cell renal cell carcinoma (ccRCC) is the most common form of kidney cancer in adults. We generated TRAnsgenic of Cancer of the Kidney (TRACK) mice that express a triple-mutant (P402A, P564A, and N803A) human HIF1α construct specifically in their proximal tubule (PT) cells. We demonstrated that the elevated lipid content found in human ccRCCs is mimicked in these TRACK PT cells. Additionally, we reported that ATF4 (activating transcription factor 4), a transcription factor, and its target genes were highly expressed both in human ccRCCs and in TRACK PT cells. To delineate the functions of ATF4 in ccRCC we have now generated TRACK mice in which the ATF4 gene is specifically deleted in PT cells (GCREA∆T). Our genome-wide transcriptomics and proteomics studies show that expression of ∼20 % of mRNAs and proteins is significantly altered in GCREA∆T compared to TRACK kidney cortices. Gene set enrichment analyses (GSEAs) of mRNAs demonstrate that the fatty acid metabolism pathway is upregulated in TRACK vs WT and that, conversely, ATF4 deletion reduces mRNAs in the fatty acid metabolism pathway (e.g., ATP citrate lyase). Moreover, some transcripts elevated in human ccRCC are reduced in GCREA∆T vs. TRACK kidney cortices and cystic, pre-cancerous lesions are also reduced. Thus, ATF4 actions increase both lipid droplet accumulation in this ccRCC model and oncogenesis-related gene expression. These data suggest that ATF4 contributes to the formation of ccRCC tumors and may be a potential therapeutic target.
{"title":"Deletion of the transcription factor ATF4 in a model of clear cell renal cell carcinoma","authors":"Yuling Chi , Shireen Chikara , Eduardo Mere Del Aguila , Tuo Zhang , Jacob B. Geri , David M. Nanus , Lorraine J. Gudas","doi":"10.1016/j.neo.2025.101188","DOIUrl":"10.1016/j.neo.2025.101188","url":null,"abstract":"<div><div>Clear cell renal cell carcinoma (ccRCC) is the most common form of kidney cancer in adults. We generated <u>TRA</u>nsgenic of <u>C</u>ancer of the <u>K</u>idney (TRACK) mice that express a triple-mutant (P402A, P564A, and N803A) human HIF1α construct specifically in their proximal tubule (PT) cells. We demonstrated that the elevated lipid content found in human ccRCCs is mimicked in these TRACK PT cells. Additionally, we reported that ATF4 (activating transcription factor 4), a transcription factor, and its target genes were highly expressed both in human ccRCCs and in TRACK PT cells. To delineate the functions of ATF4 in ccRCC we have now generated TRACK mice in which the ATF4 gene is specifically deleted in PT cells (GCREA∆T). Our genome-wide transcriptomics and proteomics studies show that expression of ∼20 % of mRNAs and proteins is significantly altered in GCREA∆T compared to TRACK kidney cortices. Gene set enrichment analyses (GSEAs) of mRNAs demonstrate that the fatty acid metabolism pathway is upregulated in TRACK vs WT and that, conversely, ATF4 deletion reduces mRNAs in the fatty acid metabolism pathway (e.g., ATP citrate lyase). Moreover, some transcripts elevated in human ccRCC are reduced in GCREA∆T vs. TRACK kidney cortices and cystic, pre-cancerous lesions are also reduced. Thus, ATF4 actions increase both lipid droplet accumulation in this ccRCC model and oncogenesis-related gene expression. These data suggest that ATF4 contributes to the formation of ccRCC tumors and may be a potential therapeutic target.</div></div>","PeriodicalId":18917,"journal":{"name":"Neoplasia","volume":"66 ","pages":"Article 101188"},"PeriodicalIF":4.8,"publicationDate":"2025-06-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144203969","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
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