Neoplasia最新文献

{"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}

{"title":"Exosomes in review: A new frontier in CAR-T cell therapies","authors":"John S. Wang ,&nbsp;Samuel J. Schellenberg ,&nbsp;Athena Demeros ,&nbsp;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}

{"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 ,&nbsp;Shenghua Zhang ,&nbsp;Xinmei Huang ,&nbsp;Qianqian Wang ,&nbsp;Weiyan Xu ,&nbsp;Jing Huang ,&nbsp;Yuming Su ,&nbsp;Qinkun Sun ,&nbsp;Xiaojuan Du ,&nbsp;Baocai Xing ,&nbsp;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}

{"title":"Exogenous BMI1 expression aggravates oral squamous cell carcinomas in tongue epithelia","authors":"Jorge Baquero ,&nbsp;Xiao-Han Tang ,&nbsp;Daniel Galke ,&nbsp;Theresa Scognamiglio ,&nbsp;Tuo Zhang ,&nbsp;Dawson Miller ,&nbsp;Qiuying Chen ,&nbsp;Steven Gross ,&nbsp;Lorraine J. Gudas","doi":"10.1016/j.neo.2025.101146","DOIUrl":"10.1016/j.neo.2025.101146","url":null,"abstract":"<div><div>Oral squamous cell carcinoma (OSCC) is characterized by aggressiveness and a poor prognosis, in part because most patients are diagnosed during the later stages of the disease. B cell-specific Moloney murine leukemia virus integration site 1 (BMI1), part of polycomb repressive complex 1 (PRC1), is a key transcription factor overexpressed in OSCC. Although increased BMI1 has been linked to tumor formation in mouse models of the disease, the molecular mechanisms have not been elucidated. Here we used a transgenic mouse line (KrTB) that selectively overexpresses BMI1 in the tongue basal epithelial stem cells (SCs) to delineate BMI1 actions during oral tumorigenesis. By tumor pathological classification after 4-nitroquinoline 1-oxide (4-NQO)-induced carcinogenesis we detected more severe tumors in mice with ectopic BMI1 expression. Genome-wide transcriptomics indicated that mRNAs associated with human OSCC, including SOX9, HIF1A, MMP9, INHBB, and MYOF, were further increased by ectopic BMI1 expression in murine tongue epithelia. mRNAs encoding multiple metabolic targets, such as SLC2A1 (GLUT1), PKM, LDHA, and HK2, were also increased upon BMI1 overexpression in 4-NQO-treated tongue epithelia. Furthermore, we detected BMI1, SOX9, and GLUT1 proteins in the infiltrating cells of invasion fronts identified by markers of invasive SCCs. Finally, metabolomic data show that BMI1 overexpression in tongue epithelia promotes glycolysis during 4-NQO-induced carcinogenesis. Thus, our data demonstrate that BMI1 causes OSCC cells to alter cell metabolism, as changes in many of these transcripts are linked to increased glycolysis and metabolic reprograming that occurs during carcinogenesis.</div></div>","PeriodicalId":18917,"journal":{"name":"Neoplasia","volume":"62 ","pages":"Article 101146"},"PeriodicalIF":4.8,"publicationDate":"2025-02-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143487605","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":"Fatty acid synthase (FASN) inhibition cooperates with BH3 mimetic drugs to overcome resistance to mitochondrial apoptosis in pancreatic cancer","authors":"Travis Vander Steen ,&nbsp;Ingrid Espinoza ,&nbsp;Cristina Duran ,&nbsp;Guillem Casadevall ,&nbsp;Eila Serrano-Hervás ,&nbsp;Elisabet Cuyàs ,&nbsp;Sara Verdura ,&nbsp;George Kemble ,&nbsp;Scott H. Kaufmann ,&nbsp;Robert McWilliams ,&nbsp;Sílvia Osuna ,&nbsp;Daniel D. Billadeau ,&nbsp;Javier A. Menendez ,&nbsp;Ruth Lupu","doi":"10.1016/j.neo.2025.101143","DOIUrl":"10.1016/j.neo.2025.101143","url":null,"abstract":"<div><div>Resistance to mitochondrial apoptosis is a major driver of chemoresistance in pancreatic ductal adenocarcinoma (PDAC). However, pharmacological manipulation of the mitochondrial apoptosis threshold in PDAC cells remains an unmet therapeutic goal. We hypothesized that fatty acid synthase inhibitors (FASNis), a family of targeted metabolic therapeutics recently entering the clinic, could lower the apoptotic threshold in chemoresistant PDAC cells and be synergistic with BH3 mimetics that neutralize anti-apoptotic proteins. Computational studies with TVB-3166 and TVB-3664, two analogues of the clinical-grade FASNi TVB-2640 (denifanstat), confirmed their uncompetitive behavior towards NADPH when bound to the FASN ketoacyl reductase domain. The extent of NADPH accumulation, a consequence of FASN inhibition, paralleled the sensitivity of PDAC cells to the apoptotic effects of TVB FASNis in conventional PDAC cell lines that naturally express varying levels of FASN. FASN inhibition dramatically increased the sensitivity of “FASN-high” expressing PDAC cells to the BCL2/BCL-X_L/BCL-W inhibitor ABT-263/navitoclax and the BCL2-selective inhibitor ABT-199/venetoclax, both <em>in vitro</em> and in <em>in vivo</em> xenografted tumors. The ability of TVB FASNis to shift the balance of pro- and anti-apoptotic proteins and thereby push PDAC cells closer to the apoptotic threshold was also observed in cell lines developed from patient-derived xenografts (PDXs) representative of the classical (pancreatic) transcriptomic subtype of PDAC. Experiments in PDAC PDXs <em>in vivo</em> confirmed the synergistic antitumor activity of TVB-3664 with navitoclax and venetoclax, independent of the nature of the replication stress signature of patient-derived PDAC cells. The discovery that targeted inhibition of FASN is a metabolic perturbation that sensitizes PDAC cells to BH3 mimetics warrants further investigation to overcome resistance to mitochondrial apoptosis in PDAC patients.</div></div>","PeriodicalId":18917,"journal":{"name":"Neoplasia","volume":"62 ","pages":"Article 101143"},"PeriodicalIF":4.8,"publicationDate":"2025-02-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143479359","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":"m6A eraser ALKBH5/treRNA1/DDX46 axis regulates BCR expression","authors":"Bandish Kapadia ,&nbsp;Anirban Roychowdhury ,&nbsp;Forum Kayastha ,&nbsp;Won Sok Lee ,&nbsp;Nahid Nanaji ,&nbsp;Jolene Windle ,&nbsp;Ronald Gartenhaus","doi":"10.1016/j.neo.2025.101144","DOIUrl":"10.1016/j.neo.2025.101144","url":null,"abstract":"<div><div>Epitranscriptomic modifications, particularly N6-methyladenosine (m6A), have emerged as critical regulators of RNA stability, localization, and translation, shaping immune responses and tumor progression. In B-cell biology, m6A modifications influence germinal center formation and antigen-driven differentiation, underscoring their importance in immune regulation. Among m6A regulators, ALKBH5 (RNA demethylase) is pivotal in removing methylation marks and modulating gene expression in diverse cellular contexts. Despite advancements in understanding m6A dynamics, the mechanistic interplay between m6A demethylation and B-cell receptor (BCR) signaling pathways still needs to be explored. This study reveals a novel regulatory axis involving ALKBH5, treRNA1 (Translation Regulatory Long Non-Coding RNA 1), and DDX46 (RNA helicase). Upon activation signals, ALKBH5 and treRNA1 translocate to the nucleus, forming a functional complex with DDX46 to orchestrate the removal of m6A modifications on key transcripts, including those involved in BCR signaling. This demethylation enhances transcript stability and facilitates cytoplasmic export through interaction with the RNA-binding protein HuR, promoting efficient translation. Disruption of this axis, via loss of ALKBH5, DDX46, or treRNA1, led to impaired transcript processing and diminished BCR-related gene expression, highlighting the critical role of m6A demethylation in maintaining RNA dynamics. These findings uncover a previously unrecognized epitranscriptomic mechanism driven by the ALKBH5-treRNA1-DDX46 complex, with significant implications for B-cell functionality, immune regulation, and oncogenic pathways. Targeting this axis offers a promising avenue for developing therapeutic strategies in cancer and immune-related disorders where m6A dysregulation plays a central role.</div></div>","PeriodicalId":18917,"journal":{"name":"Neoplasia","volume":"62 ","pages":"Article 101144"},"PeriodicalIF":4.8,"publicationDate":"2025-02-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143471167","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":"Effect of MisMatch repair deficiency on metastasis occurrence in a syngeneic mouse model","authors":"Pierre Laplante ,&nbsp;Reginaldo Rosa ,&nbsp;Laetitia Nebot-Bral ,&nbsp;Jordane Goulas ,&nbsp;Caroline Pouvelle ,&nbsp;Sergey Nikolaev ,&nbsp;Aymeric Silvin ,&nbsp;Patricia L Kannouche","doi":"10.1016/j.neo.2025.101145","DOIUrl":"10.1016/j.neo.2025.101145","url":null,"abstract":"<div><div>Mismatch repair deficiency leads to high mutation rates and microsatellite instability (MSI-H), associated with immune infiltration and responsiveness to immunotherapies. In early stages, MSI-H tumors generally have a better prognosis and lower metastatic potential than microsatellite-stable (MSS) tumors, especially in colorectal cancer. However, in advanced stages, MSI-H tumors lose this survival advantage for reasons that remain unclear. We developed a syngeneic mouse model of MSI cancer by knocking out the MMR gene <em>Msh2</em> in the metastatic 4T1 breast cancer cell line. This model mirrored genomic features of MSI-H cancers and showed reduction in metastatic incidence compared to their MSS counterparts. In MSI-H tumors, we observed an enrichment of immune gene-signatures that negatively correlated with metastasis incidence. A hybrid epithelial-mesenchymal signature, related to aggressiveness was detected only in metastatic MSI-H tumors. Interestingly, we identified immature myeloid cells at primary and metastatic sites in MSI-H tumor-bearing mice, suggesting that MMR deficiency elicits specific immune responses beyond T-cell activation.</div></div>","PeriodicalId":18917,"journal":{"name":"Neoplasia","volume":"62 ","pages":"Article 101145"},"PeriodicalIF":4.8,"publicationDate":"2025-02-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143471166","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":"Phase I clinical trial of a novel procaspase-3 activator SM-1 with temozolomide in recurrent high-grade gliomas","authors":"Mengqian Huang ,&nbsp;Zhuang Kang ,&nbsp;Shenglan Li ,&nbsp;Botao Zhang ,&nbsp;Yantao Xiao ,&nbsp;Shangwei Li ,&nbsp;Wenbin Li","doi":"10.1016/j.neo.2025.101141","DOIUrl":"10.1016/j.neo.2025.101141","url":null,"abstract":"<div><h3>Objective</h3><div>Despite a standard of care, the mortality of recurrent high-grade gliomas (HGGs) remains high. SM-1 is a novel molecular activator that has shown to target procaspase-3, which is overexpressed in HGGs. A phase I clinical trial was conducted to evaluate the safety, pharmacokinetics, and primary clinical efficacy of SM-1 plus TMZ. Participants received escalating doses of daily oral SM-1 (450, 600, and 800 mg) plus standard TMZ therapy.</div></div><div><h3>Methods</h3><div>In the preclinical study, the synergistic effects of SM-1 and temozolomide (TMZ) in rodent models were evaluated. In the clinical study, adult patients received SM-1 therapy in various doses in combination with a standard TMZ dosing. The tolerability and pharmacokinetics data of the combination therapy were tested. The primary efficacy was measured by tumor response in accordance with the RANO criteria.</div></div><div><h3>Results</h3><div>A total of 13 patients with recurrent HGG were enrolled, with 11 patients completed ≥ two cycles of therapy and received tumor assessment. Among them, one patient had complete response, whereas two patients had partial response for the best change from baseline. No dose-limited toxicities were observed, and no maximum tolerated dose was reached.</div></div><div><h3>Conclusion</h3><div>SM-1 has the potential to enhance antitumor activity while alleviating the side effects of TMZ. SM-1 exhibited mild toxicity in patients with recurrent HGG. The combination of SM-1 and TMZ warrants further investigation, with promising clinical outcomes. The monotherapy phase and expansion phase of SM-1 are still ongoing. (ClinicalTrials.gov number, CTR20221641).</div></div>","PeriodicalId":18917,"journal":{"name":"Neoplasia","volume":"61 ","pages":"Article 101141"},"PeriodicalIF":4.8,"publicationDate":"2025-02-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143437530","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}