Pub Date : 2025-01-01DOI: 10.1016/j.neo.2024.101098
Phoebe Power , Joelle P Straehla , Jason Fangusaro , Pratiti Bandopadhayay , Neevika Manoharan
The last quarter century has heralded dramatic changes in the field of pediatric neuro-oncology, with the era defined by profound developments in the understanding of the biological underpinnings of childhood central nervous system (CNS) tumors and translational therapeutics. Although there have been momentous strides forward in biologic, diagnostic, therapeutic, and experimental domains, considerable challenges remain and CNS tumors remain the leading cause of pediatric cancer-related mortality. Here, we review the significant advances in the field of pediatric neuro-oncology over the last 25 years and highlight ongoing hurdles facing future progress.
{"title":"Pediatric neuro-oncology: Highlights of the last quarter-century","authors":"Phoebe Power , Joelle P Straehla , Jason Fangusaro , Pratiti Bandopadhayay , Neevika Manoharan","doi":"10.1016/j.neo.2024.101098","DOIUrl":"10.1016/j.neo.2024.101098","url":null,"abstract":"<div><div>The last quarter century has heralded dramatic changes in the field of pediatric neuro-oncology, with the era defined by profound developments in the understanding of the biological underpinnings of childhood central nervous system (CNS) tumors and translational therapeutics. Although there have been momentous strides forward in biologic, diagnostic, therapeutic, and experimental domains, considerable challenges remain and CNS tumors remain the leading cause of pediatric cancer-related mortality. Here, we review the significant advances in the field of pediatric neuro-oncology over the last 25 years and highlight ongoing hurdles facing future progress.</div></div>","PeriodicalId":18917,"journal":{"name":"Neoplasia","volume":"59 ","pages":"Article 101098"},"PeriodicalIF":4.8,"publicationDate":"2025-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11664148/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142787444","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-11-30DOI: 10.1016/j.neo.2024.101097
Daniel Peña-Oyarzún , Andrew F.G. Quest , Lorena Lobos-González , Andrea Maturana-Ramírez , Montserrat Reyes
Oral squamous cell carcinoma (OSCC) is the most common type of oral cancer, which is usually preceded by a potentially malignant disorder histologically diagnosed as dysplasia. We and others have provided evidence for the pro-carcinogenic role of the Wnt/β-catenin pathway in this context, in which Wnt ligands stabilize and allow relocalization of β-catenin to the nucleus for transcription of pro-survival and pro-proliferation genes. However, the contribution of Porcupine (PORCN), an O-acyltransferase that catalyzes the palmitoylation of Wnt ligands, to OSCC carcinogenesis is not known. Moreover, the effectiveness of LGK974, a novel PORCN inhibitor remains to be elucidated. By using different ex vivo, in vivo and in vitro OSCC carcinogenesis models, we show that PORCN expression is significantly increased in high-grade dysplasia as well as moderately/poorly- differentiated OSCC. Consistent with these observations, expression of key proteins involved in the Wnt/β-catenin pathway are elevated as well. Importantly, the treatment with LGK974, a chemical PORCN inhibitor, reduced the number and size of oral lesions in mice treated with 4-Nitroquinoline 1-oxide (4NQO), a tobacco smoke surrogate. These results highlight the role of PORCN during OSCC carcinogenesis.
{"title":"Porcupine expression promotes the progression of oral carcinogenesis","authors":"Daniel Peña-Oyarzún , Andrew F.G. Quest , Lorena Lobos-González , Andrea Maturana-Ramírez , Montserrat Reyes","doi":"10.1016/j.neo.2024.101097","DOIUrl":"10.1016/j.neo.2024.101097","url":null,"abstract":"<div><div>Oral squamous cell carcinoma (OSCC) is the most common type of oral cancer, which is usually preceded by a potentially malignant disorder histologically diagnosed as dysplasia. We and others have provided evidence for the pro-carcinogenic role of the Wnt/β-catenin pathway in this context, in which Wnt ligands stabilize and allow relocalization of β-catenin to the nucleus for transcription of pro-survival and pro-proliferation genes. However, the contribution of Porcupine (PORCN), an O-acyltransferase that catalyzes the palmitoylation of Wnt ligands, to OSCC carcinogenesis is not known. Moreover, the effectiveness of LGK974, a novel PORCN inhibitor remains to be elucidated. By using different <em>ex vivo, in vivo</em> and <em>in vitro</em> OSCC carcinogenesis models, we show that PORCN expression is significantly increased in high-grade dysplasia as well as moderately/poorly- differentiated OSCC. Consistent with these observations, expression of key proteins involved in the Wnt/β-catenin pathway are elevated as well. Importantly, the treatment with LGK974, a chemical PORCN inhibitor, reduced the number and size of oral lesions in mice treated with 4-Nitroquinoline 1-oxide (4NQO), a tobacco smoke surrogate. These results highlight the role of PORCN during OSCC carcinogenesis.</div></div>","PeriodicalId":18917,"journal":{"name":"Neoplasia","volume":"59 ","pages":"Article 101097"},"PeriodicalIF":4.8,"publicationDate":"2024-11-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142756835","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}
X-linked inhibitor of apoptosis-associated factor 1 (XAF1) is a stress-inducible tumor suppressor that is commonly inactivated in multiple types of human malignancies. Nevertheless, the molecular basis for the XAF1-mediated tumor suppression remains largely undefined. Here, we report that XAF1 is secreted from cells under various cytotoxic stress conditions and activates T cell-mediated tumor surveillance. In cancer cells exposed to interferon , tumor necrosis factor , and etoposide, XAF1 is elevated and actively secreted through the unconventional endo-lysosomal trafficking pathway and the zinc finger 4 domain of XAF1 plays an essential for this secretion. Secreted XAF1 is internalized into nearby T cells through clathrin-mediated endocytosis and stimulates proliferation, migration, and tumor infiltration of T cells. Internalized XAF1 activates RAF-MEK-ERK signaling through the direct interaction with and phosphorylation of lymphocyte-specific protein tyrosine kinase. In response to interferon injection, Xaf1+/+ tumors display significantly higher regression rate and T cell infiltration compared to Xaf1−/− tumors while Xaf1−/− tumors are markedly reduced by injection of recombinant Xaf1. XAF1 expression is associated with overall survival in T cell-enriched cancer patients and also correlates with prognosis in T cell-based immunotherapies. Together, our study identifies XAF1 as a novel secretory immune-modulatory tumor suppressor, illuminating the mechanistic consequence of its inactivation in tumorigenesis.
{"title":"XAF1 is secreted from stressed tumor cells to activate T cell-mediated tumor surveillance via Lck-ERK signaling","authors":"Jieun Ahn, Seung-Hun Jang, Sungchan Jang, Ji-Hye Yoon, Min-Goo Lee, Sung-Gil Chi","doi":"10.1016/j.neo.2024.101094","DOIUrl":"10.1016/j.neo.2024.101094","url":null,"abstract":"<div><div>X-linked inhibitor of apoptosis-associated factor 1 (XAF1) is a stress-inducible tumor suppressor that is commonly inactivated in multiple types of human malignancies. Nevertheless, the molecular basis for the XAF1-mediated tumor suppression remains largely undefined. Here, we report that XAF1 is secreted from cells under various cytotoxic stress conditions and activates T cell-mediated tumor surveillance. In cancer cells exposed to interferon <span><math><mrow><mo>−</mo><mi>γ</mi></mrow></math></span>, tumor necrosis factor <span><math><mrow><mo>−</mo><mi>α</mi></mrow></math></span>, and etoposide, XAF1 is elevated and actively secreted through the unconventional endo-lysosomal trafficking pathway and the zinc finger 4 domain of XAF1 plays an essential for this secretion. Secreted XAF1 is internalized into nearby T cells through clathrin-mediated endocytosis and stimulates proliferation, migration, and tumor infiltration of T cells. Internalized XAF1 activates RAF-MEK-ERK signaling through the direct interaction with and phosphorylation of lymphocyte-specific protein tyrosine kinase. In response to interferon <span><math><mrow><mo>−</mo><mi>γ</mi></mrow></math></span> injection, <em>Xaf1</em><sup><em>+</em></sup><sup><em>/+</em></sup> tumors display significantly higher regression rate and T cell infiltration compared to <em>Xaf1<sup>−/−</sup></em> tumors while <em>Xaf1</em><sup>−/−</sup> tumors are markedly reduced by injection of recombinant Xaf1. XAF1 expression is associated with overall survival in T cell-enriched cancer patients and also correlates with prognosis in T cell-based immunotherapies. Together, our study identifies XAF1 as a novel secretory immune-modulatory tumor suppressor, illuminating the mechanistic consequence of its inactivation in tumorigenesis.</div></div>","PeriodicalId":18917,"journal":{"name":"Neoplasia","volume":"59 ","pages":"Article 101094"},"PeriodicalIF":4.8,"publicationDate":"2024-11-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142743804","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-11-29DOI: 10.1016/j.neo.2024.101092
Rocco Caggiano , Evgeniia Prokhorova , Lena Duma , Kira Schützenhofer , Raffaella Lauro , Giuliana Catara , Rosa Marina Melillo , Angela Celetti , Rebecca Smith , S John Weroha , Scott H Kaufmann , Ivan Ahel , Luca Palazzo
The ADP-ribosyl hydrolases PARG and ARH3 counteract PARP enzymatic activity by removing ADP-ribosylation. PARG and ARH3 activities have a synthetic lethal effect; however, the specific molecular mechanisms underlying this response remain unknown. Here, we show that the PARG and ARH3 synthetic lethality is enhanced further in the presence of DNA alkylating agents, suggesting that the inability to revert ADP-ribosylation primarily affects the repair of alkylated DNA bases. ARH3 knockout cells, treated with PARG inhibitor and alkylating genotoxins, accumulated single-stranded DNA and DNA damage, resulting in G2/M cell cycle arrest and apoptosis. Furthermore, we reveal a reduction in PARP1/PARP2 levels in ARH3-deficient cells treated with PARG inhibitor due to excessive ADP-ribosylation, which may contribute to alkylating agents’ vulnerability. Collectively, these results uncover the potential of targeting ADP-ribosyl hydrolases in combination with alkylating agents for cancer therapy and provide insights into the mechanisms underlying the synthetic lethal effect.
{"title":"Suppression of ADP-ribosylation reversal triggers cell vulnerability to alkylating agents","authors":"Rocco Caggiano , Evgeniia Prokhorova , Lena Duma , Kira Schützenhofer , Raffaella Lauro , Giuliana Catara , Rosa Marina Melillo , Angela Celetti , Rebecca Smith , S John Weroha , Scott H Kaufmann , Ivan Ahel , Luca Palazzo","doi":"10.1016/j.neo.2024.101092","DOIUrl":"10.1016/j.neo.2024.101092","url":null,"abstract":"<div><div>The ADP-ribosyl hydrolases PARG and ARH3 counteract PARP enzymatic activity by removing ADP-ribosylation. PARG and ARH3 activities have a synthetic lethal effect; however, the specific molecular mechanisms underlying this response remain unknown. Here, we show that the PARG and ARH3 synthetic lethality is enhanced further in the presence of DNA alkylating agents, suggesting that the inability to revert ADP-ribosylation primarily affects the repair of alkylated DNA bases. <em>ARH3</em> knockout cells, treated with PARG inhibitor and alkylating genotoxins, accumulated single-stranded DNA and DNA damage, resulting in G2/M cell cycle arrest and apoptosis. Furthermore, we reveal a reduction in PARP1/PARP2 levels in <em>ARH3</em>-deficient cells treated with PARG inhibitor due to excessive ADP-ribosylation, which may contribute to alkylating agents’ vulnerability. Collectively, these results uncover the potential of targeting ADP-ribosyl hydrolases in combination with alkylating agents for cancer therapy and provide insights into the mechanisms underlying the synthetic lethal effect.</div></div>","PeriodicalId":18917,"journal":{"name":"Neoplasia","volume":"59 ","pages":"Article 101092"},"PeriodicalIF":4.8,"publicationDate":"2024-11-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142743818","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-11-28DOI: 10.1016/j.neo.2024.101093
Rajsumeet S. Macwan , Giulio Ferrero , Barbara Pardini , Alessio Naccarati , Piotr B. Kozlowski , Michael J. Papetti
Objective
The high morbidity and mortality associated with colorectal cancer (CRC) and the recent increases in early-onset CRC obviate the need for novel methods to detect and treat this disease, particularly at early stages. We hypothesize that aberrant expression of genes involved in the crypt-luminal migration of colon epithelial cells, a process necessary for their growth arrest and maturation, may disrupt differentiation and transition cells from a normal to tumorigenic state.
Methods
We searched for contractility- and motility-related genes that are dysregulated in human CRC relative to normal colon. RNA expression of one such gene, tropomyosin 4 (TPM4), was measured by qRT-PCR and RNA-seq in human colorectal tissues at various stages of tumorigenesis: CRC, adenoma, and at-risk (grossly normal mucosa from a patient with Familial Adenomatous Polyposis, or FAP), relative to controls. Effects of aberrant TPM4 expression on colon epithelial cell proliferation and maturation were determined by overexpression using stable transfection in spontaneously differentiating Caco2 cells or silencing using siRNA in proliferating cells.
Results
TPM4 is overexpressed at various stages of tumorigenesis, including CRC, adenoma, and grossly normal FAP colon tissue, as well as in proliferating versus differentiating Caco2 cells. TPM4.2 overexpression in differentiating Caco2 cells markedly inhibits certain aspects of maturation, notably sucrase isomaltase and glutathione-S-transferase alpha1 expression, and causes morphological and cell junction abnormalities. Conversely, siRNA-mediated suppression of TPM4.2 inhibits Caco2 proliferation.
Conclusions
TPM4 overexpression attenuates colon epithelial cell differentiation and promotes proliferation. Therefore, TPM4 expression may be a biomarker to enhance strategies for CRC diagnosis and treatment.
目的结直肠癌（CRC）的高发病率和死亡率以及近年来早发性CRC的增加，使得对这种疾病的检测和治疗的新方法的需求，特别是在早期阶段。我们假设，参与结肠上皮细胞隐窝-腔内迁移的基因的异常表达可能会破坏细胞从正常状态向致瘤状态的分化和转化。结肠上皮细胞隐窝-腔内迁移是其生长停滞和成熟所必需的过程。方法我们在人类结直肠癌中寻找相对于正常结肠的收缩性和运动性相关基因。其中一种基因原肌球蛋白4 （TPM4）的RNA表达，通过qRT-PCR和RNA-seq在不同肿瘤发生阶段的人类结直肠组织中相对于对照组进行了测量：CRC、腺瘤和高危（来自家族性腺瘤性息肉病（FAP）患者的大体正常粘膜）。TPM4异常表达对结肠上皮细胞增殖和成熟的影响通过在自发分化的Caco2细胞中稳定转染过表达或在增殖细胞中使用siRNA沉默来确定。结果stpm4在肿瘤发生的各个阶段都过表达，包括结直肠癌、腺瘤和大体正常的FAP结肠组织，以及增殖和分化的Caco2细胞。TPM4.2在分化cca2细胞中的过表达会显著抑制成熟过程的某些方面，特别是蔗糖酶异麦芽糖酶和谷胱甘肽- s -转移酶alpha1的表达，并导致形态和细胞连接异常。相反，sirna介导的TPM4.2抑制可抑制Caco2增殖。结论stpm4过表达可减缓结肠上皮细胞分化，促进细胞增殖。因此，TPM4的表达可能是一种生物标志物，可以增强CRC的诊断和治疗策略。
{"title":"TPM4 overexpression drives colon epithelial cell tumorigenesis by suppressing differentiation and promoting proliferation","authors":"Rajsumeet S. Macwan , Giulio Ferrero , Barbara Pardini , Alessio Naccarati , Piotr B. Kozlowski , Michael J. Papetti","doi":"10.1016/j.neo.2024.101093","DOIUrl":"10.1016/j.neo.2024.101093","url":null,"abstract":"<div><h3>Objective</h3><div>The high morbidity and mortality associated with colorectal cancer (CRC) and the recent increases in early-onset CRC obviate the need for novel methods to detect and treat this disease, particularly at early stages. We hypothesize that aberrant expression of genes involved in the crypt-luminal migration of colon epithelial cells, a process necessary for their growth arrest and maturation, may disrupt differentiation and transition cells from a normal to tumorigenic state.</div></div><div><h3>Methods</h3><div>We searched for contractility- and motility-related genes that are dysregulated in human CRC relative to normal colon. RNA expression of one such gene, tropomyosin 4 (<em>TPM4</em>), was measured by qRT-PCR and RNA-seq in human colorectal tissues at various stages of tumorigenesis: CRC, adenoma, and at-risk (grossly normal mucosa from a patient with Familial Adenomatous Polyposis, or FAP), relative to controls. Effects of aberrant <em>TPM4</em> expression on colon epithelial cell proliferation and maturation were determined by overexpression using stable transfection in spontaneously differentiating Caco2 cells or silencing using siRNA in proliferating cells.</div></div><div><h3>Results</h3><div><em>TPM4</em> is overexpressed at various stages of tumorigenesis, including CRC, adenoma, and grossly normal FAP colon tissue, as well as in proliferating versus differentiating Caco2 cells. <em>TPM4.2</em> overexpression in differentiating Caco2 cells markedly inhibits certain aspects of maturation, notably sucrase isomaltase and glutathione-S-transferase alpha1 expression, and causes morphological and cell junction abnormalities. Conversely, siRNA-mediated suppression of <em>TPM4.2</em> inhibits Caco2 proliferation.</div></div><div><h3>Conclusions</h3><div><em>TPM4</em> overexpression attenuates colon epithelial cell differentiation and promotes proliferation. Therefore, <em>TPM4</em> expression may be a biomarker to enhance strategies for CRC diagnosis and treatment.</div></div>","PeriodicalId":18917,"journal":{"name":"Neoplasia","volume":"59 ","pages":"Article 101093"},"PeriodicalIF":4.8,"publicationDate":"2024-11-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142743805","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-11-27DOI: 10.1016/j.neo.2024.101086
Adrian Fehn , Adrian von Witzleben , Ayla Grages , Tsima Abou Kors , Jasmin Ezić , Annika C. Betzler , Cornelia Brunner , Patrick J. Schuler , Marie-Nicole Theodoraki , Thomas K. Hoffmann , Simon Laban
Failure of immunotherapy in head and neck squamous cell carcinoma (HNSCC) patients represents an unmet need to augment leverage of adaptive immunity. Immunogenic cancer-testis antigen (CTA) expression as well as lymphocyte differentiation and function are regulated by DNA methylation. Therefore, epigenetic therapy via inhibition of DNA-Methyltransferases by 5-Aza-2′-deoxycytidine (DAC) serves a promising adjuvant in immunotherapy.
We investigated the effects of DAC on CTA expression and proliferative capacity in HNSCC cell lines and on the expression of 12 immune checkpoint molecules (ICM) on lymphocytes of oropharyngeal squamous cell carcinoma (OPSCC) patients and healthy donors.
In all cell lines CTA were upregulated accompanied by decreased proliferation. In lymphocytes pronounced alterations of the ICM repertoire were observed, influenced by donor type and subpopulation. On CD39+ CD4 and CD8 T cells, the expression of co-stimulatory ICM GITR and OX40 increased dose dependently, whereas expression decreased on CD39- CD4 T cells. PD1 expression increased primarily on CD39+ CD8 T cells and decreased on CD39- CD4 T cells. CD27 expression decreased primarily in CD8 T cells, but increased in CD39- CD4 T cells, whereas ICOS expression was lowered in both CD39+ and CD39- subsets of CD4 as well as CD8 T cells.
DAC treatment increased immunogenicity and decreased proliferation in HNSCC cells while enhancing expression of co-stimulatory ICM GITR and OX40. We propose low dose DAC treatment as a adjuvant to immunotherapy.
{"title":"5-Aza-2′-deoxycytidin (Decitabine) increases cancer-testis antigen expression in head and neck squamous cell carcinoma and modifies immune checkpoint expression, especially in CD39-positive CD8 and CD4 T cells","authors":"Adrian Fehn , Adrian von Witzleben , Ayla Grages , Tsima Abou Kors , Jasmin Ezić , Annika C. Betzler , Cornelia Brunner , Patrick J. Schuler , Marie-Nicole Theodoraki , Thomas K. Hoffmann , Simon Laban","doi":"10.1016/j.neo.2024.101086","DOIUrl":"10.1016/j.neo.2024.101086","url":null,"abstract":"<div><div>Failure of immunotherapy in head and neck squamous cell carcinoma (HNSCC) patients represents an unmet need to augment leverage of adaptive immunity. Immunogenic cancer-testis antigen (CTA) expression as well as lymphocyte differentiation and function are regulated by DNA methylation. Therefore, epigenetic therapy via inhibition of DNA-Methyltransferases by 5-Aza-2′-deoxycytidine (DAC) serves a promising adjuvant in immunotherapy.</div><div>We investigated the effects of DAC on CTA expression and proliferative capacity in HNSCC cell lines and on the expression of 12 immune checkpoint molecules (ICM) on lymphocytes of oropharyngeal squamous cell carcinoma (OPSCC) patients and healthy donors.</div><div>In all cell lines CTA were upregulated accompanied by decreased proliferation. In lymphocytes pronounced alterations of the ICM repertoire were observed, influenced by donor type and subpopulation. On CD39+ CD4 and CD8 T cells, the expression of co-stimulatory ICM GITR and OX40 increased dose dependently, whereas expression decreased on CD39- CD4 T cells. PD1 expression increased primarily on CD39+ CD8 T cells and decreased on CD39- CD4 T cells. CD27 expression decreased primarily in CD8 T cells, but increased in CD39- CD4 T cells, whereas ICOS expression was lowered in both CD39+ and CD39- subsets of CD4 as well as CD8 T cells.</div><div>DAC treatment increased immunogenicity and decreased proliferation in HNSCC cells while enhancing expression of co-stimulatory ICM GITR and OX40. We propose low dose DAC treatment as a adjuvant to immunotherapy.</div></div>","PeriodicalId":18917,"journal":{"name":"Neoplasia","volume":"59 ","pages":"Article 101086"},"PeriodicalIF":4.8,"publicationDate":"2024-11-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142721167","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-11-25DOI: 10.1016/j.neo.2024.101090
Christina Michail, Fernando Rodrigues Lima, Mireille Viguier, Frédérique Deshayes
SETD2 is known to be the unique histone methyltransferase responsible for the trimethylation of the lysine 36 of histone H3 thus generating H3K36me3. This epigenetic mark is critical for transcriptional activation and elongation, DNA repair, mRNA splicing, and DNA methylation. Recurrent SETD2-inactivating mutations and altered H3K36me3 levels are found in cancer at high frequency and numerous studies indicate that SETD2 acts as a tumor suppressor. Recently, SETD2 was further shown to methylate non-histone proteins particularly the cytoskeletal proteins tubulin and actin with subsequent impacts on cytoskeleton structure, mitosis and cell migration.
Herein, we provide a review of the role of SETD2 in different cancers with special emphasis on the structural basis of the functions of this key lysine methyltransferase. Moreover, beyond the role of this enzyme in epigenetics and H3K36me3-dependent processes, we highlight the putative role of "non-epigenetic/H3K36me3" functions of SETD2 in cancer, particularly those involving the cytoskeleton.
{"title":"Structure and function of the lysine methyltransferase SETD2 in cancer: From histones to cytoskeleton","authors":"Christina Michail, Fernando Rodrigues Lima, Mireille Viguier, Frédérique Deshayes","doi":"10.1016/j.neo.2024.101090","DOIUrl":"10.1016/j.neo.2024.101090","url":null,"abstract":"<div><div>SETD2 is known to be the unique histone methyltransferase responsible for the trimethylation of the lysine 36 of histone H3 thus generating H3K36me3. This epigenetic mark is critical for transcriptional activation and elongation, DNA repair, mRNA splicing, and DNA methylation. Recurrent SETD2-inactivating mutations and altered H3K36me3 levels are found in cancer at high frequency and numerous studies indicate that SETD2 acts as a tumor suppressor. Recently, SETD2 was further shown to methylate non-histone proteins particularly the cytoskeletal proteins tubulin and actin with subsequent impacts on cytoskeleton structure, mitosis and cell migration.</div><div>Herein, we provide a review of the role of SETD2 in different cancers with special emphasis on the structural basis of the functions of this key lysine methyltransferase. Moreover, beyond the role of this enzyme in epigenetics and H3K36me3-dependent processes, we highlight the putative role of \"non-epigenetic/H3K36me3\" functions of SETD2 in cancer, particularly those involving the cytoskeleton.</div></div>","PeriodicalId":18917,"journal":{"name":"Neoplasia","volume":"59 ","pages":"Article 101090"},"PeriodicalIF":4.8,"publicationDate":"2024-11-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142702719","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}
Dedifferentiated liposarcoma (DDLPS) comprises a high-grade dedifferentiated (DD) component and a juxtaposed well-differentiated (WD) component. The DD component is believed to originate from the WD component by acquiring additional genomic alterations. In this study, we performed multiregion genome, epigenome, and transcriptome analyses of three patients with DDLPS. In two patients, there were few common genomic alterations across all samples, but many common alterations within DD or WD component samples. Phylogenetic trees predicted from the genomic alterations were consistent with those predicted from DNA methylation patterns. The expression patterns of adipogenesis-related genes differed between DD and WD components and also among patients in connection with their CpG island methylation status. These results indicate that in some patients, WD and DD components are evolutionarily separated at very early stages of tumorigenesis, and are formed through relatively long clonal selection with acquisition of different driver genomic alterations and DNA methylation changes.
{"title":"Early separation and parallel clonal selection of dedifferentiated and well-differentiated components in dedifferentiated liposarcoma","authors":"Tetsuya Sekita , Naofumi Asano , Takashi Kubo , Hirohiko Totsuka , Sachiyo Mitani , Naoko Hattori , Akihiko Yoshida , Eisuke Kobayashi , Motokiyo Komiyama , Toshikazu Ushijima , Robert Nakayama , Masaya Nakamura , Akira Kawai , Hitoshi Ichikawa","doi":"10.1016/j.neo.2024.101074","DOIUrl":"10.1016/j.neo.2024.101074","url":null,"abstract":"<div><div>Dedifferentiated liposarcoma (DDLPS) comprises a high-grade dedifferentiated (DD) component and a juxtaposed well-differentiated (WD) component. The DD component is believed to originate from the WD component by acquiring additional genomic alterations. In this study, we performed multiregion genome, epigenome, and transcriptome analyses of three patients with DDLPS. In two patients, there were few common genomic alterations across all samples, but many common alterations within DD or WD component samples. Phylogenetic trees predicted from the genomic alterations were consistent with those predicted from DNA methylation patterns. The expression patterns of adipogenesis-related genes differed between DD and WD components and also among patients in connection with their CpG island methylation status. These results indicate that in some patients, WD and DD components are evolutionarily separated at very early stages of tumorigenesis, and are formed through relatively long clonal selection with acquisition of different driver genomic alterations and DNA methylation changes.</div></div>","PeriodicalId":18917,"journal":{"name":"Neoplasia","volume":"59 ","pages":"Article 101074"},"PeriodicalIF":4.8,"publicationDate":"2024-11-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142702720","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-11-22DOI: 10.1016/j.neo.2024.101081
Chinthalapally V Rao , Altaf Mohammed , Naveena B Janakiram , Qian Li , Rebekah L Ritchie , Stan Lightfoot , Awasthi Vibhudutta , Vernon E Steele
{"title":"Corrigendum to “Inhibition of Pancreatic Intraepithelial Neoplasia Progression to Carcinoma by Nitric Oxide-Releasing Aspirin in p48Cre/+-LSL-KrasG12D/+ Mice” [Neoplasia, Volume 14, Issue 9 (2012) 778-787]","authors":"Chinthalapally V Rao , Altaf Mohammed , Naveena B Janakiram , Qian Li , Rebekah L Ritchie , Stan Lightfoot , Awasthi Vibhudutta , Vernon E Steele","doi":"10.1016/j.neo.2024.101081","DOIUrl":"10.1016/j.neo.2024.101081","url":null,"abstract":"","PeriodicalId":18917,"journal":{"name":"Neoplasia","volume":"59 ","pages":"Article 101081"},"PeriodicalIF":4.8,"publicationDate":"2024-11-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142693077","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-11-22DOI: 10.1016/j.neo.2024.101088
Ruichen Huang , Qiao Zhou , Jiajun Liu , Yang Xia , Yang Jiao , Bi Zhao , Tangtao Feng , Haosu Zhou , Xiuyan Song , Hao Qin , Jun Wang , Lan Cheng , Yunye Ning , Qinying Sun , Yanfang Liu , Xiaoping Su , Yuchao Dong , Wei Zhang
Background
The neoantigen vaccine has remarkable potential in treating advanced cancer due to its tumor specificity and ability to bypass central tolerance mechanisms. However, numerous neoantigens show poor immunogenicity, and the immune inhibitory factors of present in both tumors and tumor-draining lymph nodes impair the efficacy of cancer neoantigen vaccine. Eliminating immunosuppressive cells will improve the priming and expansion of anti-tumor immune cells induced by the vaccine.
Methods
In this study, a Treg-depleting regimen (consisting of CD25mAb and low-dose cyclophosphamide (LD-CTX)) was used in conjunction with a neoantigen vaccine for treating mice with solid tumors. We constructed two types of tumor models and investigated differences in therapy efficacy in the four groups (PBS, vaccine, CD25mAb+CTX and combination) at the genetic and protein levels. ELISPOT and TCR sequencing were applied to detect the expansion of neoantigen reactive T cells (NRT) and tumor antigen spreading.
Results
In the combinational group, the ELISPOT results showed an obvious expansion of NRT cells induced by weak immunogenic peptides. The combinational group exhibited significant improvement in inhibiting the tumor growth extended the survival time of tumor-bearing mice, and promoted T cells infiltration into tumors. Besides, compared to the Vac group, more neoantigen-targeted and TAA-targeted T cells were detected in the combinational group by TCR sequencing. The results of transcriptomic sequencing and flow cytometry showed that the number of Tregs in the combinational group was lower, while the proportions of memory effector T cells and effector T cells were higher than those in the vaccine group. An increase in mature DCs was also observed in vaccinated mice after receiving this Treg-depleting strategy.
Conclusion
Our research first revealed that inhibiting the normal function of Tregs transformed “weaker” neoantigens into “stronger” ones, while also contributing to the proliferation of NRT cells. This Treg-depleting strategy allowed neoantigens with poor immunogenicity to elicit a robust immune response, thereby augmenting the efficacy of the neoantigen vaccine in delaying tumor growth and prolonging the survival of the hosts.
背景：新抗原疫苗因其肿瘤特异性和绕过中枢耐受机制的能力，在治疗晚期癌症方面具有显著的潜力。然而，许多新抗原的免疫原性较差，肿瘤和肿瘤引流淋巴结中存在的免疫抑制因子也会影响癌症新抗原疫苗的疗效。消除免疫抑制细胞将改善疫苗诱导的抗肿瘤免疫细胞的启动和扩增：在这项研究中，Treg清除疗法（由CD25mAb和低剂量环磷酰胺（LD-CTX）组成）与新抗原疫苗联合用于治疗实体瘤小鼠。我们构建了两种类型的肿瘤模型，并在基因和蛋白质水平上研究了四组（PBS、疫苗、CD25mAb+CTX 和组合）的疗效差异。应用ELISPOT和TCR测序检测新抗原反应性T细胞（NRT）的扩增和肿瘤抗原的扩散：联合组的 ELISPOT 结果显示，弱免疫原性肽诱导的新抗原反应性 T 细胞明显扩增。联合组在抑制肿瘤生长、延长肿瘤小鼠存活时间和促进 T 细胞浸润肿瘤方面均有明显改善。此外，与Vac组相比，联合组通过TCR测序检测到了更多的新抗原靶向T细胞和TAA靶向T细胞。转录组测序和流式细胞术结果显示，联合组中Tregs的数量低于疫苗组，而记忆效应T细胞和效应T细胞的比例高于疫苗组。结论：我们的研究首先揭示了抑制Treg和T效应细胞对免疫系统的影响：我们的研究首次发现，抑制 Tregs 的正常功能可将 "较弱 "的新抗原转化为 "较强 "的新抗原，同时还有助于 NRT 细胞的增殖。这种抑制Treg的策略使免疫原性较差的新抗原引起了强有力的免疫反应，从而增强了新抗原疫苗在延缓肿瘤生长和延长宿主生存期方面的功效。
{"title":"Depletion of regulatory T cells enhances the T cell response induced by the neoantigen vaccine with weak immunogenicity","authors":"Ruichen Huang , Qiao Zhou , Jiajun Liu , Yang Xia , Yang Jiao , Bi Zhao , Tangtao Feng , Haosu Zhou , Xiuyan Song , Hao Qin , Jun Wang , Lan Cheng , Yunye Ning , Qinying Sun , Yanfang Liu , Xiaoping Su , Yuchao Dong , Wei Zhang","doi":"10.1016/j.neo.2024.101088","DOIUrl":"10.1016/j.neo.2024.101088","url":null,"abstract":"<div><h3>Background</h3><div>The neoantigen vaccine has remarkable potential in treating advanced cancer due to its tumor specificity and ability to bypass central tolerance mechanisms. However, numerous neoantigens show poor immunogenicity, and the immune inhibitory factors of present in both tumors and tumor-draining lymph nodes impair the efficacy of cancer neoantigen vaccine. Eliminating immunosuppressive cells will improve the priming and expansion of anti-tumor immune cells induced by the vaccine.</div></div><div><h3>Methods</h3><div>In this study, a Treg-depleting regimen (consisting of CD25mAb and low-dose cyclophosphamide (LD-CTX)) was used in conjunction with a neoantigen vaccine for treating mice with solid tumors. We constructed two types of tumor models and investigated differences in therapy efficacy in the four groups (PBS, vaccine, CD25mAb+CTX and combination) at the genetic and protein levels. ELISPOT and TCR sequencing were applied to detect the expansion of neoantigen reactive T cells (NRT) and tumor antigen spreading.</div></div><div><h3>Results</h3><div>In the combinational group, the ELISPOT results showed an obvious expansion of NRT cells induced by weak immunogenic peptides. The combinational group exhibited significant improvement in inhibiting the tumor growth extended the survival time of tumor-bearing mice, and promoted T cells infiltration into tumors. Besides, compared to the Vac group, more neoantigen-targeted and TAA-targeted T cells were detected in the combinational group by TCR sequencing. The results of transcriptomic sequencing and flow cytometry showed that the number of Tregs in the combinational group was lower, while the proportions of memory effector T cells and effector T cells were higher than those in the vaccine group. An increase in mature DCs was also observed in vaccinated mice after receiving this Treg-depleting strategy.</div></div><div><h3>Conclusion</h3><div>Our research first revealed that inhibiting the normal function of Tregs transformed “weaker” neoantigens into “stronger” ones, while also contributing to the proliferation of NRT cells. This Treg-depleting strategy allowed neoantigens with poor immunogenicity to elicit a robust immune response, thereby augmenting the efficacy of the neoantigen vaccine in delaying tumor growth and prolonging the survival of the hosts.</div></div>","PeriodicalId":18917,"journal":{"name":"Neoplasia","volume":"59 ","pages":"Article 101088"},"PeriodicalIF":4.8,"publicationDate":"2024-11-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142695963","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}
扫码关注我们
求助内容：
应助结果提醒方式：
京公网安备 11010802042870号