Neoplasia最新文献_第2页

Exogenous BMI1 expression aggravates oral squamous cell carcinomas in tongue epithelia

IF 4.8 2区医学 Q1 Biochemistry, Genetics and Molecular Biology

Neoplasia

Pub Date : 2025-02-25 DOI: 10.1016/j.neo.2025.101146

Jorge Baquero , Xiao-Han Tang , Daniel Galke , Theresa Scognamiglio , Tuo Zhang , Dawson Miller , Qiuying Chen , Steven Gross , Lorraine J. Gudas

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.

{"title":"Exogenous BMI1 expression aggravates oral squamous cell carcinomas in tongue epithelia","authors":"Jorge Baquero , Xiao-Han Tang , Daniel Galke , Theresa Scognamiglio , Tuo Zhang , Dawson Miller , Qiuying Chen , Steven Gross , 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}

引用次数: 0

Fatty acid synthase (FASN) inhibition cooperates with BH3 mimetic drugs to overcome resistance to mitochondrial apoptosis in pancreatic cancer

IF 4.8 2区医学 Q1 Biochemistry, Genetics and Molecular Biology

Neoplasia

Pub Date : 2025-02-24 DOI: 10.1016/j.neo.2025.101143

Travis Vander Steen , Ingrid Espinoza , Cristina Duran , Guillem Casadevall , Eila Serrano-Hervás , Elisabet Cuyàs , Sara Verdura , George Kemble , Scott H. Kaufmann , Robert McWilliams , Sílvia Osuna , Daniel D. Billadeau , Javier A. Menendez , Ruth Lupu

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 in vitro and in in vivo 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 in vivo 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.

{"title":"Fatty acid synthase (FASN) inhibition cooperates with BH3 mimetic drugs to overcome resistance to mitochondrial apoptosis in pancreatic cancer","authors":"Travis Vander Steen , Ingrid Espinoza , Cristina Duran , Guillem Casadevall , Eila Serrano-Hervás , Elisabet Cuyàs , Sara Verdura , George Kemble , Scott H. Kaufmann , Robert McWilliams , Sílvia Osuna , Daniel D. Billadeau , Javier A. Menendez , 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<sub>L</sub>/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}

引用次数: 0

m6A eraser ALKBH5/treRNA1/DDX46 axis regulates BCR expression

IF 4.8 2区医学 Q1 Biochemistry, Genetics and Molecular Biology

Neoplasia

Pub Date : 2025-02-22 DOI: 10.1016/j.neo.2025.101144

Bandish Kapadia , Anirban Roychowdhury , Forum Kayastha , Won Sok Lee , Nahid Nanaji , Jolene Windle , Ronald Gartenhaus

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.

{"title":"m6A eraser ALKBH5/treRNA1/DDX46 axis regulates BCR expression","authors":"Bandish Kapadia , Anirban Roychowdhury , Forum Kayastha , Won Sok Lee , Nahid Nanaji , Jolene Windle , 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}

引用次数: 0

Effect of MisMatch repair deficiency on metastasis occurrence in a syngeneic mouse model

IF 4.8 2区医学 Q1 Biochemistry, Genetics and Molecular Biology

Neoplasia

Pub Date : 2025-02-21 DOI: 10.1016/j.neo.2025.101145

Pierre Laplante , Reginaldo Rosa , Laetitia Nebot-Bral , Jordane Goulas , Caroline Pouvelle , Sergey Nikolaev , Aymeric Silvin , Patricia L Kannouche

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 Msh2 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.

{"title":"Effect of MisMatch repair deficiency on metastasis occurrence in a syngeneic mouse model","authors":"Pierre Laplante , Reginaldo Rosa , Laetitia Nebot-Bral , Jordane Goulas , Caroline Pouvelle , Sergey Nikolaev , Aymeric Silvin , 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}

引用次数: 0

Phase I clinical trial of a novel procaspase-3 activator SM-1 with temozolomide in recurrent high-grade gliomas

IF 4.8 2区医学 Q1 Biochemistry, Genetics and Molecular Biology

Neoplasia

Pub Date : 2025-02-18 DOI: 10.1016/j.neo.2025.101141

Mengqian Huang , Zhuang Kang , Shenglan Li , Botao Zhang , Yantao Xiao , Shangwei Li , Wenbin Li

Objective

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.

Methods

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.

Results

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.

Conclusion

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).

{"title":"Phase I clinical trial of a novel procaspase-3 activator SM-1 with temozolomide in recurrent high-grade gliomas","authors":"Mengqian Huang , Zhuang Kang , Shenglan Li , Botao Zhang , Yantao Xiao , Shangwei Li , 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}

引用次数: 0

Identification of 68 HLA-A24 and -A2-restricted cytotoxic T lymphocyte-inducing peptides derived from 10 common cancer-specific antigens frequently expressed in various solid cancers

IF 4.8 2区医学 Q1 Biochemistry, Genetics and Molecular Biology

Neoplasia

Pub Date : 2025-02-11 DOI: 10.1016/j.neo.2025.101135

Hiroki Kinoshita , Kazumasa Takenouchi , Nobuo Tsukamoto , Kazunobu Ohnuki , Toshihiro Suzuki , Tetsuya Nakatsura

Targeting cancer antigens expressed in cancer cells is necessary to develop cancer-specific immunotherapy. We have performed immunohistochemical analysis of various solid cancer specimens, adding ROBO1, AFP, TGFBI, EphB4, CLDN1, and LAT1 to the previously studied glypican-3 (GPC3), HSP105α, FOXM1, and SPARC, and found that these 10 common cancer antigens are sufficient to cover most solid cancers. These antigens were frequently expressed in various solid cancers but shown to be rarely ex-pressed, with some exceptions, in non-cancerous normal organs adjacent to the cancer. In this study, we predicted 72 and 73 peptides that bind to HLA-A24 and -A2 in silico from the full-length amino acid sequences of these 10 common cancer antigens and immunized each HLA transgenic mouse with a cocktail of synthesized peptides together with the poly I:CLC three times weekly to analyze the antigen-specific immune response. As a result, 68 peptide sequences (30 and 38, respectively) were identified that had higher cytotoxic T lymphocyte (CTL) induction ability than GPC3 298-306 and GPC3 144-152 used in the clinical trials. Furthermore, experiments with cocktail peptide vaccines using mouse models expressing subcutaneous tumors of each antigen showed promising results in terms of safety and efficacy. These peptides identified in this study, derived from 10 common cancer antigens covering all solid cancers, are expected to be clinically applicable as cocktail peptide vaccines.

{"title":"Identification of 68 HLA-A24 and -A2-restricted cytotoxic T lymphocyte-inducing peptides derived from 10 common cancer-specific antigens frequently expressed in various solid cancers","authors":"Hiroki Kinoshita , Kazumasa Takenouchi , Nobuo Tsukamoto , Kazunobu Ohnuki , Toshihiro Suzuki , Tetsuya Nakatsura","doi":"10.1016/j.neo.2025.101135","DOIUrl":"10.1016/j.neo.2025.101135","url":null,"abstract":"<div><div>Targeting cancer antigens expressed in cancer cells is necessary to develop cancer-specific immunotherapy. We have performed immunohistochemical analysis of various solid cancer specimens, adding ROBO1, AFP, TGFBI, EphB4, CLDN1, and LAT1 to the previously studied glypican-3 (GPC3), HSP105α, FOXM1, and SPARC, and found that these 10 common cancer antigens are sufficient to cover most solid cancers. These antigens were frequently expressed in various solid cancers but shown to be rarely ex-pressed, with some exceptions, in non-cancerous normal organs adjacent to the cancer. In this study, we predicted 72 and 73 peptides that bind to HLA-A24 and -A2 <em>in silico</em> from the full-length amino acid sequences of these 10 common cancer antigens and immunized each HLA transgenic mouse with a cocktail of synthesized peptides together with the poly I:CLC three times weekly to analyze the antigen-specific immune response. As a result, 68 peptide sequences (30 and 38, respectively) were identified that had higher cytotoxic T lymphocyte (CTL) induction ability than GPC3 298-306 and GPC3 144-152 used in the clinical trials. Furthermore, experiments with cocktail peptide vaccines using mouse models expressing subcutaneous tumors of each antigen showed promising results in terms of safety and efficacy. These peptides identified in this study, derived from 10 common cancer antigens covering all solid cancers, are expected to be clinically applicable as cocktail peptide vaccines.</div></div>","PeriodicalId":18917,"journal":{"name":"Neoplasia","volume":"61 ","pages":"Article 101135"},"PeriodicalIF":4.8,"publicationDate":"2025-02-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143388263","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}

引用次数: 0

MYH knockdown in pancreatic cancer cells creates an exploitable DNA repair vulnerability

IF 4.8 2区医学 Q1 Biochemistry, Genetics and Molecular Biology

Neoplasia

Pub Date : 2025-02-11 DOI: 10.1016/j.neo.2025.101138

James Ephraums , Janet Youkhana , Aparna S. Raina , Grace Schulstad , Kento Croft , Amanda Mawson , John Kokkinos , Estrella Gonzales-Aloy , Rosa Mistica C. Ignacio , Joshua A. McCarroll , Cyrille Boyer , David Goldstein , Marina Pajic , Koroush S. Haghighi , Amber Johns , Anthony J. Gill , Mert Erkan , Australian Pancreatic Cancer Genome Initiative (APGI) , Phoebe A. Phillips , George Sharbeen

Pancreatic ductal adenocarcinoma (PDAC) has a poor 5-year survival rate of just 13 %. Conventional therapies fail due to acquired chemoresistance. We previously identified MutY-Homolog (MYH), a protein that repairs oxidative DNA damage, as a therapeutic target that induces apoptosis in PDAC cells. However, we did not understand the mechanism driving these anti-PDAC effects, nor did we have a means to therapeutically inhibit MYH. In this study, we demonstrated that MYH inhibition induces DNA damage and checkpoint activation in PDAC cells. Using a clinically-relevant PDAC mouse model, we showed that therapeutic MYH-siRNA delivery using Star 3 nanoparticles increased intratumoural PDAC cell death, but did not inhibit tumour growth. Finally, we showed that MYH knockdown in PDAC cells sensitised them to the anti-proliferative and anti-clonogenic effects of oxaliplatin and olaparib. Our findings identify a potential novel therapeutic approach for PDAC that induces a therapeutically exploitable DNA repair vulnerability.

{"title":"MYH knockdown in pancreatic cancer cells creates an exploitable DNA repair vulnerability","authors":"James Ephraums , Janet Youkhana , Aparna S. Raina , Grace Schulstad , Kento Croft , Amanda Mawson , John Kokkinos , Estrella Gonzales-Aloy , Rosa Mistica C. Ignacio , Joshua A. McCarroll , Cyrille Boyer , David Goldstein , Marina Pajic , Koroush S. Haghighi , Amber Johns , Anthony J. Gill , Mert Erkan , Australian Pancreatic Cancer Genome Initiative (APGI) , Phoebe A. Phillips , George Sharbeen","doi":"10.1016/j.neo.2025.101138","DOIUrl":"10.1016/j.neo.2025.101138","url":null,"abstract":"<div><div>Pancreatic ductal adenocarcinoma (PDAC) has a poor 5-year survival rate of just 13 %. Conventional therapies fail due to acquired chemoresistance. We previously identified MutY-Homolog (MYH), a protein that repairs oxidative DNA damage, as a therapeutic target that induces apoptosis in PDAC cells. However, we did not understand the mechanism driving these anti-PDAC effects, nor did we have a means to therapeutically inhibit MYH. In this study, we demonstrated that MYH inhibition induces DNA damage and checkpoint activation in PDAC cells. Using a clinically-relevant PDAC mouse model, we showed that therapeutic MYH-siRNA delivery using Star 3 nanoparticles increased intratumoural PDAC cell death, but did not inhibit tumour growth. Finally, we showed that MYH knockdown in PDAC cells sensitised them to the anti-proliferative and anti-clonogenic effects of oxaliplatin and olaparib. Our findings identify a potential novel therapeutic approach for PDAC that induces a therapeutically exploitable DNA repair vulnerability.</div></div>","PeriodicalId":18917,"journal":{"name":"Neoplasia","volume":"61 ","pages":"Article 101138"},"PeriodicalIF":4.8,"publicationDate":"2025-02-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143388266","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}

引用次数: 0

Disruption of redox balance in glutaminolytic triple negative breast cancer by inhibition of glutaminase and glutamate export

IF 4.8 2区医学 Q1 Biochemistry, Genetics and Molecular Biology

Neoplasia

Pub Date : 2025-02-11 DOI: 10.1016/j.neo.2025.101136

Hoon Choi , Mamta Gupta , Arjun Sengupta , Emma E. Furth , Christopher Hensley , Aalim M. Weljie , Hsiaoju Lee , Yu-Ting Lu , Austin Pantel , David Mankoff , Rong Zhou

Resistance to chemotherapy is an important challenge in the clinical management of triple-negative breast cancer (TNBC). Utilization of the amino acid glutamine as a key nutrient is a metabolic signature of TNBC featuring high glutaminase (GLS) activity and a large pool of cellular glutamate, which mediates intracellular enrichment of cystine via xCT (SLC7A11) antiporter activity. To overcome chemo-resistant TNBC, we identified a strategy of dual metabolic inhibition of GLS and xCT to sensitize resistant TNBC cells to chemotherapy. We successfully tested this strategy in a human TNBC line and its chemoresistant variant in vitro and their xenograft models in vivo. Key findings of our study include: 1. Dual metabolic inhibition induced pronounced reductions of cellular glutathione accompanying significant increases of cellular superoxide level in both parent and resistant TNBC cells. While GLS and xCT inhibition did not directly kill cells via apoptosis, they potentiated doxorubicin (DOX) and cisplatin (CIS) to induce remarkably higher levels of apoptosis than DOX or CIS alone. 2. Although the resistant TNBC cells exhibited higher capacity to mitigate oxidative stress than the parent cells, their resistance was overcome by dual metabolic inhibition combined with DOX or CIS. 3. In vivo efficacy and safety of the triple combination (GLS and xCT inhibition plus DOX or CIS) were demonstrated in both chemo sensitive and resistant TNBC tumors in mice. In conclusion, GLS and xCT inhibition resulted in unmitigated oxidative stress due to depletion of glutathione, representing a promising strategy to overcome chemoresistance in glutamine-dependent TNBC.

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引用次数: 0

STAT signaling in the pathogenesis and therapy of acute myeloid leukemia and myelodysplastic syndromes

IF 4.8 2区医学 Q1 Biochemistry, Genetics and Molecular Biology

Neoplasia

Pub Date : 2025-02-10 DOI: 10.1016/j.neo.2025.101137

Zoe King , Sudhamsh Reddy Desai , David A. Frank , Aditi Shastri

Acute myeloid leukemia (AML) and myelodysplastic syndromes (MDS) represent complex hematopoietic malignancies characterized by ineffective hematopoiesis and dysregulated myeloid differentiation. Recent research has underscored the critical role of aberrant STAT signaling pathways, particularly involving STAT3 and STAT5, in the pathogenesis of these disorders. Aberrant activation of STAT proteins has been implicated as a mediator of oncogenesis in several malignancies. In this review, we discuss the role of STAT proteins in both regulated and dysregulated hematopoiesis, the consequences of dysregulation in acute myeloid leukemia and myelodysplastic syndromes, therapeutic strategies, and recent advancements in STAT-targeted therapy. By integrating findings from recent preclinical and clinical studies, this review provides insights into the evolving landscape of STAT-targeted therapies, highlighting the promise of these approaches in enhancing treatment efficacy and improving patient outcomes in high-risk hematologic malignancies.

引用次数: 0

Cancer stem-like cells stay in a plastic state ready for tumor evolution

IF 4.8 2区医学 Q1 Biochemistry, Genetics and Molecular Biology

Neoplasia

Pub Date : 2025-02-06 DOI: 10.1016/j.neo.2025.101134

Jiali Xu , Houde Zhang , Zhihao Nie , Wenyou He , Yichao Zhao , Zhenhui Huang , Lin Jia , Zhiye Du , Baotong Zhang , Siyuan Xia

Cell plasticity emerges as a novel cancer hallmark and is pivotal in driving tumor heterogeneity and adaptive resistance to different therapies. Cancer stem-like cells (CSCs) are considered the root of cancer. While first defined as tumor-initiating cells with the potential to develop a heterogeneous tumor, CSCs further demonstrate their roles in cancer metastasis and adaptive therapeutic resistance. Generally, CSCs come from the malignant transformation of somatic stem cells or the de-differentiation of other cancer cells. The resultant cells gain more plasticity and are ready to differentiate into different cell states, enabling them to adapt to therapies and metastatic ecosystems. Therefore, CSCs are likely the nature of tumor cells that gain cell plasticity. However, the phenotypic plasticity of CSCs has never been systematically discussed. Here, we review the distinct intrinsic signaling pathways and unique microenvironmental niches that endow CSC plasticity in solid tumors to adapt to stressful conditions, as well as emerging opportunities for CSC-targeted therapy.

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引用次数: 0