Cancer gene therapy最新文献

{"title":"Proteomic profiling reveals ACSS2 facilitating metabolic support in acute myeloid leukemia","authors":"Liliana H. Mochmann, Denise Treue, Michael Bockmayr, Patricia Silva, Christin Zasada, Guido Mastrobuoni, Safak Bayram, Martin Forbes, Philipp Jurmeister, Sven Liebig, Olga Blau, Konstanze Schleich, Bianca Splettstoesser, Thierry M. Nordmann, Eva K. von der Heide, Konstandina Isaakidis, Veronika Schulze, Caroline Busch, Hafsa Siddiq, Cornelia Schlee, Svenja Hester, Lars Fransecky, Martin Neumann, Stefan Kempa, Frederick Klauschen, Claudia D. Baldus","doi":"10.1038/s41417-024-00785-5","DOIUrl":"10.1038/s41417-024-00785-5","url":null,"abstract":"Acute myeloid leukemia (AML) is a heterogeneous disease characterized by genomic aberrations in oncogenes, cytogenetic abnormalities, and an aberrant epigenetic landscape. Nearly 50% of AML cases will relapse with current treatment. A major source of therapy resistance is the interaction of mesenchymal stroma with leukemic cells resulting in therapeutic protection. We aimed to determine pro-survival/anti-apoptotic protein networks involved in the stroma protection of leukemic cells. Proteomic profiling of cultured primary AML (n = 14) with Hs5 stroma cell line uncovered an up-regulation of energy-favorable metabolic proteins. Next, we modulated stroma-induced drug resistance with an epigenetic drug library, resulting in reduced apoptosis with histone deacetylase inhibitor (HDACi) treatment versus other epigenetic modifying compounds. Quantitative phosphoproteomic probing of this effect further revealed a metabolic-enriched phosphoproteome including significant up-regulation of acetyl-coenzyme A synthetase (ACSS2, S30) in leukemia-stroma HDACi treated cocultures compared with untreated monocultures. Validating these findings, we show ACSS2 substrate, acetate, promotes leukemic proliferation, ACSS2 knockout in leukemia cells inhibits leukemic proliferation and ACSS2 knockout in the stroma impairs leukemic metabolic fitness. Finally, we identify ACSS1/ACSS2-high expression AML subtype correlating with poor overall survival. Collectively, this study uncovers the leukemia-stroma phosphoproteome emphasizing a role for ACSS2 in mediating AML growth and drug resistance.","PeriodicalId":9577,"journal":{"name":"Cancer gene therapy","volume":"31 9","pages":"1344-1356"},"PeriodicalIF":4.8,"publicationDate":"2024-06-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.com/articles/s41417-024-00785-5.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141293135","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Integrating system biology and intratumor gene therapy by trans-complementing the appropriate co-stimulatory molecule as payload in oncolytic herpes virus","authors":"A. Finizio, P. Pagano, A. Napolano, G. Froechlich, L. Infante, A. De Chiara, S. Amiranda, E. Vitiello, S. Totaro, C. Capasso, M. Raia, A. M. D’Alise, P. de Candia, N. Zambrano, E. Sasso","doi":"10.1038/s41417-024-00790-8","DOIUrl":"10.1038/s41417-024-00790-8","url":null,"abstract":"Systems biology has been applied at the multi-scale level within the cancer field, improving cancer prevention, diagnosis and enabling precision medicine approaches. While systems biology can expand the knowledge and skills for oncological treatment, it also represents a challenging expedition due to cancer complexity, heterogeneity and diversity not only between different cancer indications, but also in its evolution process through space and time. Here, by characterizing the transcriptional perturbations of the tumor microenvironment induced by oncolytic, we aimed to rationally design a novel armed oncolytic herpes virus. We found that intratumor oncovirotherapy with HSV-1 induces T-cell activation signatures and transcriptionally activates several costimulatory molecules. We identified differentially expressed costimulatory receptors and binding partners, where inducible co-stimulators (ICOS) resulted in the potentially most beneficial targeted therapy. Through an ex-vivo transcriptomic analysis, we explored the potential of arming an oncolytic virus as a combination therapy strategy; in particular, we engineered a targeted herpes virus encoding ICOSL (THV_ICOSL), which resulted in a significant improvement in tumor size control compared to unarmed parental virus. Also, combination with a PD-1 inhibitor enhanced antitumor efficacy as predictable by upregulation of PD-1 and ligands pair (PD-L1/PD-L2) upon oncolytic virus injection. Generation of the human version of this virus encoding hICOSL orthologue effectively and specifically activated human T cells by triggering the ICOS pathway. Our data support the data-driven generation of armed oncolytic viruses as combination immunotherapeutic with checkpoint inhibitors.","PeriodicalId":9577,"journal":{"name":"Cancer gene therapy","volume":"31 9","pages":"1335-1343"},"PeriodicalIF":4.8,"publicationDate":"2024-06-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.com/articles/s41417-024-00790-8.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141257602","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Retraction Note: miR-182 regulates trastuzumab resistance by targeting MET in breast cancer cells","authors":"Dan Yue, Xiaosong Qin","doi":"10.1038/s41417-024-00787-3","DOIUrl":"10.1038/s41417-024-00787-3","url":null,"abstract":"","PeriodicalId":9577,"journal":{"name":"Cancer gene therapy","volume":"31 7","pages":"1103-1103"},"PeriodicalIF":4.8,"publicationDate":"2024-06-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.com/articles/s41417-024-00787-3.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141261209","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Regulatory roles of N6-methyladenosine (m6A) methylation in RNA processing and non-communicable diseases","authors":"Faiz Ali Khan, Bernard Nsengimana, Usman Ayub Awan, Xin-Ying Ji, Shaoping Ji, Jingcheng Dong","doi":"10.1038/s41417-024-00789-1","DOIUrl":"10.1038/s41417-024-00789-1","url":null,"abstract":"Post-transcriptional RNA modification is an emerging epigenetic control mechanism in cells that is important in many different cellular and organismal processes. N6-methyladenosine (m6A) is one of the most prevalent, prolific, and ubiquitous internal transcriptional alterations in eukaryotic mRNAs, making it an important topic in the field of Epigenetics. m6A methylation acts as a dynamical regulatory process that regulates the activity of genes and participates in multiple physiological processes, by supporting multiple aspects of essential mRNA metabolic processes, including pre-mRNA splicing, nuclear export, translation, miRNA synthesis, and stability. Extensive research has linked aberrations in m6A modification and m6A-associated proteins to a wide range of human diseases. However, the impact of m6A on mRNA metabolism and its pathological connection between m6A and other non-communicable diseases, including cardiovascular disease, neurodegenerative disorders, liver diseases, and cancer remains in fragmentation. Here, we review the existing understanding of the overall role of mechanisms by which m6A exerts its activities and address new discoveries that highlight m6A’s diverse involvement in gene expression regulation. We discuss m6A deposition on mRNA and its consequences on degradation, translation, and transcription, as well as m6A methylation of non-coding chromosomal-associated RNA species. This study could give new information about the molecular process, early detection, tailored treatment, and predictive evaluation of human non-communicable diseases like cancer. We also explore more about new data that suggests targeting m6A regulators in diseases may have therapeutic advantages.","PeriodicalId":9577,"journal":{"name":"Cancer gene therapy","volume":"31 10","pages":"1439-1453"},"PeriodicalIF":4.8,"publicationDate":"2024-06-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.com/articles/s41417-024-00789-1.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141257788","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Manipulating the tumour immune microenvironment by N6-methyladenosine RNA modification","authors":"Xinyu Sun, Huirong Wang, Xi Pu, Yuting Wu, Xiao Yuan, Xu Wang, Hanqiang Lu","doi":"10.1038/s41417-024-00791-7","DOIUrl":"10.1038/s41417-024-00791-7","url":null,"abstract":"N6-methyladenosine (m6A), a posttranscriptional regulatory mechanism, is the most common epigenetic modification in mammalian mRNA. M6A modifications play a crucial role in the developmental network of immune cells. The expression of m6A-related regulators often affects carcinogenesis and tumour suppression networks. In the tumour microenvironment, m6A-modified enzymes can affect the occurrence and progression of tumours by regulating the activation and invasion of tumour-associated immune cells. Immunotherapy, which utilises immune cells, has been demonstrated to be a powerful weapon in tumour treatment and is increasingly being used in the clinic. Here, we provide an updated and comprehensive overview of how m6A modifications affect invasive immune cells and their potential role in immune regulation. In addition, we summarise the regulation of epigenetic regulators associated with m6A modifications in tumour cells on the antitumour response of immune cells in the tumour immune microenvironment. These findings provide new insights into the role of m6A modifications in the immune response and tumour development, leading to the development of novel immunotherapies for cancer treatment.","PeriodicalId":9577,"journal":{"name":"Cancer gene therapy","volume":"31 9","pages":"1315-1322"},"PeriodicalIF":4.8,"publicationDate":"2024-06-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141247553","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"H3.3-G34W in giant cell tumor of bone functionally aligns with the exon choice repressor hnRNPA1L2","authors":"Eunbi Lee, Yoon Jung Park, Anders M. Lindroth","doi":"10.1038/s41417-024-00776-6","DOIUrl":"10.1038/s41417-024-00776-6","url":null,"abstract":"RNA processing is an essential post-transcriptional phenomenon that provides the necessary complexity of transcript diversity prior to translation. Aberrations in this process could contribute to tumourigenesis, and we have previously reported increased splicing alterations in giant cell tumor of bone (GCTB), which carries mutations in the histone variant H3.3 encoding glycine 34 substituted for tryptophan (H3.3-G34W). G34W interacts with several splicing factors, most notably the trans-acting splicing factor hnRNPA1L2. To gain a deeper understanding of RNA processing in GCTB and isogenic HeLa cells with H3.3-G34W, we generated RNA-immunoprecipitation sequencing data from hnRNPA1L2 and H3.3-G34W associated RNAs, which showed that 80% overlapped across genic regions and were frequently annotated as E2F transcription factor binding sites. Splicing aberrations in both GCTB and HeLa cells with H3.3-G34W were significantly enriched for known hnRNPA1L2 binding motifs (p value < 0.01). This splicing aberration differed from hnRNPA1L2 knockouts, which showed alterations independent of H3.3-G34W. Of functional significance, hnRNPA1L2 was redistributed to closely match the H3.3 pattern, likely driven by G34W, and to loci not occupied in normal parental cells. Taken together, our data reveal a functional overlap between hnRNPA1L2 and H3.3-G34W with likely significant consequences for RNA processing during GCTB pathogenesis. This provides novel opportunities for therapeutic intervention in future modus operandi.","PeriodicalId":9577,"journal":{"name":"Cancer gene therapy","volume":"31 8","pages":"1177-1185"},"PeriodicalIF":4.8,"publicationDate":"2024-05-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.com/articles/s41417-024-00776-6.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141169366","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Unveiling mitochondrial and ribosomal gene deregulation and tumor microenvironment dynamics in acute myeloid leukemia","authors":"Chao Ma, Yuchao Hao, Bo Shi, Zheng Wu, Di Jin, Xiao Yu, Bilian Jin","doi":"10.1038/s41417-024-00788-2","DOIUrl":"10.1038/s41417-024-00788-2","url":null,"abstract":"Acute myeloid leukemia (AML) is a malignant clonal hematopoietic disease with a poor prognosis. Understanding the interaction between leukemic cells and the tumor microenvironment (TME) can help predict the prognosis of leukemia and guide its treatment. Re-analyzing the scRNA-seq data from the CSC and G20 cohorts, using a Python-based pipeline including machine-learning-based scVI-tools, recapitulated the distinct hierarchical structure within the samples of AML patients. Weighted correlation network analysis (WGCNA) was conducted to construct a weighted gene co-expression network and to identify gene modules primarily focusing on hematopoietic stem cells (HSCs), multipotent progenitors (MPPs), and natural killer (NK) cells. The analysis revealed significant deregulation in gene modules associated with aerobic respiration and ribosomal/cytoplasmic translation. Cell–cell communications were elucidated by the CellChat package, revealing an imbalance of activating and inhibitory immune signaling pathways. Interception of genes upregulated in leukemic HSCs & MPPs as well as in NKG2A-high NK cells was used to construct prognostic models. Normal Cox and artificial neural network models based on 10 genes were developed. The study reveals the deregulation of mitochondrial and ribosomal genes in AML patients and suggests the co-occurrence of stimulatory and inhibitory factors in the AML TME.","PeriodicalId":9577,"journal":{"name":"Cancer gene therapy","volume":"31 7","pages":"1034-1048"},"PeriodicalIF":4.8,"publicationDate":"2024-05-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141161045","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"CircPKN2 promotes ferroptosis in bladder cancer by promoting the ubiquitination of Stearoyl-CoA Desaturase 1","authors":"Changkun Liu, Zhuo Zou, Shengming Lu, Kun Jin, Ye Shen, Tianbao Huang, Weijian Li, Guangchen Zhou","doi":"10.1038/s41417-024-00784-6","DOIUrl":"10.1038/s41417-024-00784-6","url":null,"abstract":"Bladder cancer (BC) is one of the most common malignancies in the male urinary system and currently lacks an optimal treatment strategy. To elucidate the pathogenic mechanisms of BC from the perspective of circular RNAs, we conducted this study. Building upon our previous research, a novel circRNA, circPKN2, captured our interest due to its significant downregulation in BC, and its close association with the prognosis of BC patients. Our research findings indicate that circPKN2 can inhibit the proliferation and migration of BC cells in vitro. Furthermore, we discovered that circPKN2 exerts its anti-cancer effects in BC by promoting ferroptosis. Mechanistic studies revealed that circPKN2 recruits STUB1 to facilitate the ubiquitination of SCD1, thereby suppressing the WNT pathway and promoting ferroptosis in BC. Additionally, our research unveiled the regulatory role of the splicing factor QKI in the biogenesis of circPKN2. Animal studies demonstrated that circPKN2 enhances ferroptosis in BC cells in vivo, inhibiting tumor growth and metastasis. The discovery of the anti-cancer factor circPKN2 holds promise for providing new therapeutic targets in the prevention and treatment of BC.","PeriodicalId":9577,"journal":{"name":"Cancer gene therapy","volume":"31 8","pages":"1251-1265"},"PeriodicalIF":4.8,"publicationDate":"2024-05-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141157884","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Hsa_circ_0007590/PTBP1 complex reprograms glucose metabolism by reducing the stability of m6A-modified PTEN mRNA in pancreatic ductal adenocarcinoma","authors":"Dandan Zheng, Wenying Chen, Juanfei Peng, Xianxian Huang, Shineng Zhang, Yanyan Zhuang","doi":"10.1038/s41417-024-00786-4","DOIUrl":"10.1038/s41417-024-00786-4","url":null,"abstract":"The role of circular RNAs (circRNAs) in glucose metabolism in pancreatic duct adenocarcinoma (PDAC) remains elusive. Through RNA sequencing of cells cultured under conditions of glucose deprivation, we identified hsa_circ_0007590. Sanger sequencing and RNase R and Act D treatments were performed to confirm the circular RNA features of hsa_circ_0007590. RNA in situ hybridization (RNA-ISH) and quantitative reverse transcription PCR (qRT-PCR) were used to estimate hsa_circ_0007590 expression in PDAC clinical specimens and cell lines. hsa_circ_0007590 expression was higher in PDAC patients and closely related to the clinicopathological characteristics of the disease. Cytoplasm‒nuclear fractionation and FISH assays demonstrated that hsa_circ_0007590 was located in the nucleus. Gain-of-function and loss-of-function assays were performed to assess the biological behaviors of PDAC cells. Seahorse XF assays were performed to validate the Warburg effect. hsa_circ_0007590 facilitated the proliferation, migration, and invasion of PDAC cells and promoted the Warburg effect. Mass spectrometry, RNA pulldown, RNA immunoprecipitation (RIP), RNA m6A quantification, m6A dot blot, MeRIP, and Western blotting were conducted to investigate the detailed mechanism through which hsa_circ_0007590 produces these effects. Mechanistically, hsa_circ_0007590 targeted PTBP1 and increased the expression of the m6A reader protein YTHDF2, leading to PTEN mRNA degradation and PI3K/AKT/mTOR pathway activation. Overall, hsa_circ_0007590, which targets PTBP1, reprograms glucose metabolism by attenuating the stability of m6A-modified PTEN mRNA and holds potential promise as a therapeutic target for PDAC.","PeriodicalId":9577,"journal":{"name":"Cancer gene therapy","volume":"31 7","pages":"1090-1102"},"PeriodicalIF":4.8,"publicationDate":"2024-05-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141157888","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"IGF2BP2-modified circular RNA circCHD7 promotes endometrial cancer progression via stabilizing PDGFRB and activating JAK/STAT signaling pathway","authors":"Rui Shi, Rong Zhao, Yan Shen, Sitian Wei, Tangansu Zhang, Jun Zhang, Wan Shu, Shuangshuang Cheng, Hua Teng, Hongbo Wang","doi":"10.1038/s41417-024-00781-9","DOIUrl":"10.1038/s41417-024-00781-9","url":null,"abstract":"Circular RNAs (circRNAs) represent a class of covalently closed, single-stranded RNAs and have been linked to cancer progression. N6-methyladenosine (m6A) methylation is a ubiquitous RNA modification in cancer cells. Increasing evidence suggests that m6A can mediate the effects of circRNAs in cancer biology. In contrast, the post-transcriptional systems of m6A and circRNA in the progression of endometrial cancer (EC) remain obscure. The current study identified a novel circRNA with m6A modification, hsa_circ_0084582 (circCHD7), which was upregulated in EC tissues. Functionally, circCHD7 was found to promote the proliferation of EC cells. Mechanistically, circCHD7 interacted with insulin-like growth factor 2 mRNA-binding protein (IGF2BP2) to amplify its enrichment. Moreover, circCHD7 increased the mRNA stability of platelet-derived growth factor receptor beta (PDGFRB) in an m6A-dependent manner, thereby enhancing its expression. In addition, the circCHD7/IGF2BP2/PDGFRB axis activated the JAK/STAT signaling pathway and promoted EC cell proliferation. In conclusion, these findings provide new insights into the regulation of circRNA-mediated m6A modification, and the new “circCHD7-PDGFRB” model of regulation offers new perspectives on circCHD7 as a potential target for EC therapy.","PeriodicalId":9577,"journal":{"name":"Cancer gene therapy","volume":"31 8","pages":"1221-1236"},"PeriodicalIF":4.8,"publicationDate":"2024-05-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.com/articles/s41417-024-00781-9.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141080965","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}