Pub Date : 2024-10-30DOI: 10.1186/s12943-024-02164-y
Jing Yan, Di Chen, Zi Ye, Xuqiang Zhu, Xueyuan Li, Henan Jiao, Mengjiao Duan, Chaoli Zhang, Jingliang Cheng, Lixia Xu, Hongjiang Li, Dongming Yan
Tryptophan (Trp) metabolism involves three primary pathways: the kynurenine (Kyn) pathway (KP), the 5-hydroxytryptamine (serotonin, 5-HT) pathway, and the indole pathway. Under normal physiological conditions, Trp metabolism plays crucial roles in regulating inflammation, immunity, and neuronal function. Key rate-limiting enzymes such as indoleamine-2,3-dioxygenase (IDO), Trp-2,3-dioxygenase (TDO), and kynurenine monooxygenase (KMO) drive these metabolic processes. Imbalances in Trp metabolism are linked to various cancers and often correlate with poor prognosis and adverse clinical characteristics. Dysregulated Trp metabolism fosters tumor growth and immune evasion primarily by creating an immunosuppressive tumor microenvironment (TME). Activation of the KP results in the production of immunosuppressive metabolites like Kyn, which modulate immune responses and promote oncogenesis mainly through interaction with the aryl hydrocarbon receptor (AHR). Targeting Trp metabolism therapeutically has shown significant potential, especially with the development of small-molecule inhibitors for IDO1, TDO, and other key enzymes. These inhibitors disrupt the immunosuppressive signals within the TME, potentially restoring effective anti-tumor immune responses. Recently, IDO1 inhibitors have been tested in clinical trials, showing the potential to enhance the effects of existing cancer therapies. However, mixed results in later-stage trials underscore the need for a deeper understanding of Trp metabolism and its complex role in cancer. Recent advancements have also explored combining Trp metabolism inhibitors with other treatments, such as immune checkpoint inhibitors, chemotherapy, and radiotherapy, to enhance therapeutic efficacy and overcome resistance mechanisms. This review summarizes the current understanding of Trp metabolism and signaling in cancer, detailing the oncogenic mechanisms and clinical significance of dysregulated Trp metabolism. Additionally, it provides insights into the challenges in developing Trp-targeted therapies and future research directions aimed at optimizing these therapeutic strategies and improving patient outcomes.
{"title":"Molecular mechanisms and therapeutic significance of Tryptophan Metabolism and signaling in cancer","authors":"Jing Yan, Di Chen, Zi Ye, Xuqiang Zhu, Xueyuan Li, Henan Jiao, Mengjiao Duan, Chaoli Zhang, Jingliang Cheng, Lixia Xu, Hongjiang Li, Dongming Yan","doi":"10.1186/s12943-024-02164-y","DOIUrl":"https://doi.org/10.1186/s12943-024-02164-y","url":null,"abstract":"Tryptophan (Trp) metabolism involves three primary pathways: the kynurenine (Kyn) pathway (KP), the 5-hydroxytryptamine (serotonin, 5-HT) pathway, and the indole pathway. Under normal physiological conditions, Trp metabolism plays crucial roles in regulating inflammation, immunity, and neuronal function. Key rate-limiting enzymes such as indoleamine-2,3-dioxygenase (IDO), Trp-2,3-dioxygenase (TDO), and kynurenine monooxygenase (KMO) drive these metabolic processes. Imbalances in Trp metabolism are linked to various cancers and often correlate with poor prognosis and adverse clinical characteristics. Dysregulated Trp metabolism fosters tumor growth and immune evasion primarily by creating an immunosuppressive tumor microenvironment (TME). Activation of the KP results in the production of immunosuppressive metabolites like Kyn, which modulate immune responses and promote oncogenesis mainly through interaction with the aryl hydrocarbon receptor (AHR). Targeting Trp metabolism therapeutically has shown significant potential, especially with the development of small-molecule inhibitors for IDO1, TDO, and other key enzymes. These inhibitors disrupt the immunosuppressive signals within the TME, potentially restoring effective anti-tumor immune responses. Recently, IDO1 inhibitors have been tested in clinical trials, showing the potential to enhance the effects of existing cancer therapies. However, mixed results in later-stage trials underscore the need for a deeper understanding of Trp metabolism and its complex role in cancer. Recent advancements have also explored combining Trp metabolism inhibitors with other treatments, such as immune checkpoint inhibitors, chemotherapy, and radiotherapy, to enhance therapeutic efficacy and overcome resistance mechanisms. This review summarizes the current understanding of Trp metabolism and signaling in cancer, detailing the oncogenic mechanisms and clinical significance of dysregulated Trp metabolism. Additionally, it provides insights into the challenges in developing Trp-targeted therapies and future research directions aimed at optimizing these therapeutic strategies and improving patient outcomes.","PeriodicalId":19000,"journal":{"name":"Molecular Cancer","volume":"17 1","pages":""},"PeriodicalIF":37.3,"publicationDate":"2024-10-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142541573","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-10-30DOI: 10.1186/s12943-024-02147-z
Clare E. Murray, Anand V. R. Kornepati, Carlos Ontiveros, Yiji Liao, Bárbara de la Peña Avalos, Cody M. Rogers, Zexuan Liu, Yilun Deng, Haiyan Bai, Suresh Kari, Alvaro S. Padron, Jacob T. Boyd, Ryan Reyes, Curtis A. Clark, Robert S. Svatek, Rong Li, Yanfen Hu, Meiling Wang, José R. Conejo-Garcia, Lauren A. Byers, Kavya Ramkumar, Anil K. Sood, Jung-Min Lee, Christin E. Burd, Ratna K. Vadlamudi, Harshita B. Gupta, Weixing Zhao, Eloïse Dray, Patrick Sung, Tyler J. Curiel
Aside from the canonical role of PDL1 as a tumour surface-expressed immune checkpoint molecule, tumour-intrinsic PDL1 signals regulate non-canonical immunopathological pathways mediating treatment resistance whose significance, mechanisms, and therapeutic targeting remain incompletely understood. Recent reports implicate tumour-intrinsic PDL1 signals in the DNA damage response (DDR), including promoting homologous recombination DNA damage repair and mRNA stability of DDR proteins, but many mechanistic details remain undefined. We genetically depleted PDL1 from transplantable mouse and human cancer cell lines to understand consequences of tumour-intrinsic PDL1 signals in the DNA damage response. We complemented this work with studies of primary human tumours and inducible mouse tumours. We developed novel approaches to show tumour-intrinsic PDL1 signals in specific subcellular locations. We pharmacologically depleted tumour PDL1 in vivo in mouse models with repurposed FDA-approved drugs for proof-of-concept clinical translation studies. We show that tumour-intrinsic PDL1 promotes the checkpoint kinase-2 (Chk2)-mediated DNA damage response. Intracellular but not surface-expressed PDL1 controlled Chk2 protein content post-translationally and independently of PD1 by antagonising PIRH2 E3 ligase-mediated Chk2 polyubiquitination and protein degradation. Genetic tumour PDL1 depletion specifically reduced tumour Chk2 content but not ATM, ATR, or Chk1 DDR proteins, enhanced Chk1 inhibitor (Chk1i) synthetic lethality in vitro in diverse human and murine tumour models, and improved Chk1i efficacy in vivo. Pharmacologic tumour PDL1 depletion with cefepime or ceftazidime replicated genetic tumour PDL1 depletion by reducing tumour Chk2, inducing Chk1i synthetic lethality in a tumour PDL1-dependent manner, and reducing in vivo tumour growth when combined with Chk1i. Our data challenge the prevailing surface PDL1 paradigm, elucidate important and previously unappreciated roles for tumour-intrinsic PDL1 in regulating the ATM/Chk2 DNA damage response axis and E3 ligase-mediated protein degradation, suggest tumour PDL1 as a biomarker for Chk1i efficacy, and support the rapid clinical potential of pharmacologic tumour PDL1 depletion to treat selected cancers.
{"title":"Tumour-intrinsic PDL1 signals regulate the Chk2 DNA damage response in cancer cells and mediate resistance to Chk1 inhibitors","authors":"Clare E. Murray, Anand V. R. Kornepati, Carlos Ontiveros, Yiji Liao, Bárbara de la Peña Avalos, Cody M. Rogers, Zexuan Liu, Yilun Deng, Haiyan Bai, Suresh Kari, Alvaro S. Padron, Jacob T. Boyd, Ryan Reyes, Curtis A. Clark, Robert S. Svatek, Rong Li, Yanfen Hu, Meiling Wang, José R. Conejo-Garcia, Lauren A. Byers, Kavya Ramkumar, Anil K. Sood, Jung-Min Lee, Christin E. Burd, Ratna K. Vadlamudi, Harshita B. Gupta, Weixing Zhao, Eloïse Dray, Patrick Sung, Tyler J. Curiel","doi":"10.1186/s12943-024-02147-z","DOIUrl":"https://doi.org/10.1186/s12943-024-02147-z","url":null,"abstract":"Aside from the canonical role of PDL1 as a tumour surface-expressed immune checkpoint molecule, tumour-intrinsic PDL1 signals regulate non-canonical immunopathological pathways mediating treatment resistance whose significance, mechanisms, and therapeutic targeting remain incompletely understood. Recent reports implicate tumour-intrinsic PDL1 signals in the DNA damage response (DDR), including promoting homologous recombination DNA damage repair and mRNA stability of DDR proteins, but many mechanistic details remain undefined. We genetically depleted PDL1 from transplantable mouse and human cancer cell lines to understand consequences of tumour-intrinsic PDL1 signals in the DNA damage response. We complemented this work with studies of primary human tumours and inducible mouse tumours. We developed novel approaches to show tumour-intrinsic PDL1 signals in specific subcellular locations. We pharmacologically depleted tumour PDL1 in vivo in mouse models with repurposed FDA-approved drugs for proof-of-concept clinical translation studies. We show that tumour-intrinsic PDL1 promotes the checkpoint kinase-2 (Chk2)-mediated DNA damage response. Intracellular but not surface-expressed PDL1 controlled Chk2 protein content post-translationally and independently of PD1 by antagonising PIRH2 E3 ligase-mediated Chk2 polyubiquitination and protein degradation. Genetic tumour PDL1 depletion specifically reduced tumour Chk2 content but not ATM, ATR, or Chk1 DDR proteins, enhanced Chk1 inhibitor (Chk1i) synthetic lethality in vitro in diverse human and murine tumour models, and improved Chk1i efficacy in vivo. Pharmacologic tumour PDL1 depletion with cefepime or ceftazidime replicated genetic tumour PDL1 depletion by reducing tumour Chk2, inducing Chk1i synthetic lethality in a tumour PDL1-dependent manner, and reducing in vivo tumour growth when combined with Chk1i. Our data challenge the prevailing surface PDL1 paradigm, elucidate important and previously unappreciated roles for tumour-intrinsic PDL1 in regulating the ATM/Chk2 DNA damage response axis and E3 ligase-mediated protein degradation, suggest tumour PDL1 as a biomarker for Chk1i efficacy, and support the rapid clinical potential of pharmacologic tumour PDL1 depletion to treat selected cancers.","PeriodicalId":19000,"journal":{"name":"Molecular Cancer","volume":"5 1","pages":""},"PeriodicalIF":37.3,"publicationDate":"2024-10-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142541566","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Background: In the ongoing battle against BCR-ABL+ leukemia, despite significant advances with tyrosine kinase inhibitors (TKIs), the persistent challenges of drug resistance and the enduring presence of leukemic stem cells (LSCs) remain formidable barriers to achieving a cure.
Methods: In this study, we demonstrated that Disulfiram (DSF) induces ferroptosis to synergize with TKIs in inhibiting BCR-ABL+ cells, particularly targeting resistant cells and LSCs, using cell models, mouse models, and primary cells from patients. We elucidated the mechanism by which DSF promotes GPX4 degradation to induce ferroptosis through immunofluorescence, co-immunoprecipitation (CO-IP), RNA sequencing, lipid peroxidation assays, and rescue experiments.
Results: Here, we present compelling evidence elucidating the sensitivity of DSF, an USA FDA-approved drug for alcohol dependence, towards BCR-ABL+ cells. Our findings underscore DSF's ability to selectively induce a potent cytotoxic effect on BCR-ABL+ cell lines and effectively inhibit primary BCR-ABL+ leukemia cells. Crucially, the combined treatment of DSF with TKIs selectively eradicates TKI-insensitive stem cells and resistant cells. Of particular note is DSF's capacity to disrupt GPX4 stability, elevate the labile iron pool, and intensify lipid peroxidation, ultimately leading to ferroptotic cell death. Our investigation shows that BCR-ABL expression induces alterations in cellular iron metabolism and increases GPX4 expression. Additionally, we demonstrate the indispensability of GPX4 for LSC development and the initiation/maintenance of BCR-ABL+ leukemia. Mechanical analysis further elucidates DSF's capacity to overcome resistance by reducing GPX4 levels through the disruption of its binding with HSPA8, thereby promoting STUB1-mediated GPX4 ubiquitination and subsequent proteasomal degradation. Furthermore, the combined treatment of DSF with TKIs effectively targets both BCR-ABL+ blast cells and drug-insensitive LSCs, conferring a significant survival advantage in mouse models.
Conclusion: In summary, the dual inhibition of GPX4 and BCR-ABL presents a promising therapeutic strategy to synergistically target blast cells and drug-insensitive LSCs in patients, offering potential avenues for advancing leukemia treatment.
{"title":"Combined targeting of GPX4 and BCR-ABL tyrosine kinase selectively compromises BCR-ABL+ leukemia stem cells.","authors":"Chengwu Zeng, Dingrui Nie, Xianfeng Wang, Shuxin Zhong, Xiangbo Zeng, Xin Liu, Kangjie Qiu, Xueting Peng, Wenyi Zhang, Shengting Chen, Xianfeng Zha, Cunte Chen, Zhenhua Chen, Weizhang Wang, Yangqiu Li","doi":"10.1186/s12943-024-02162-0","DOIUrl":"10.1186/s12943-024-02162-0","url":null,"abstract":"<p><strong>Background: </strong>In the ongoing battle against BCR-ABL+ leukemia, despite significant advances with tyrosine kinase inhibitors (TKIs), the persistent challenges of drug resistance and the enduring presence of leukemic stem cells (LSCs) remain formidable barriers to achieving a cure.</p><p><strong>Methods: </strong>In this study, we demonstrated that Disulfiram (DSF) induces ferroptosis to synergize with TKIs in inhibiting BCR-ABL+ cells, particularly targeting resistant cells and LSCs, using cell models, mouse models, and primary cells from patients. We elucidated the mechanism by which DSF promotes GPX4 degradation to induce ferroptosis through immunofluorescence, co-immunoprecipitation (CO-IP), RNA sequencing, lipid peroxidation assays, and rescue experiments.</p><p><strong>Results: </strong>Here, we present compelling evidence elucidating the sensitivity of DSF, an USA FDA-approved drug for alcohol dependence, towards BCR-ABL+ cells. Our findings underscore DSF's ability to selectively induce a potent cytotoxic effect on BCR-ABL+ cell lines and effectively inhibit primary BCR-ABL+ leukemia cells. Crucially, the combined treatment of DSF with TKIs selectively eradicates TKI-insensitive stem cells and resistant cells. Of particular note is DSF's capacity to disrupt GPX4 stability, elevate the labile iron pool, and intensify lipid peroxidation, ultimately leading to ferroptotic cell death. Our investigation shows that BCR-ABL expression induces alterations in cellular iron metabolism and increases GPX4 expression. Additionally, we demonstrate the indispensability of GPX4 for LSC development and the initiation/maintenance of BCR-ABL+ leukemia. Mechanical analysis further elucidates DSF's capacity to overcome resistance by reducing GPX4 levels through the disruption of its binding with HSPA8, thereby promoting STUB1-mediated GPX4 ubiquitination and subsequent proteasomal degradation. Furthermore, the combined treatment of DSF with TKIs effectively targets both BCR-ABL+ blast cells and drug-insensitive LSCs, conferring a significant survival advantage in mouse models.</p><p><strong>Conclusion: </strong>In summary, the dual inhibition of GPX4 and BCR-ABL presents a promising therapeutic strategy to synergistically target blast cells and drug-insensitive LSCs in patients, offering potential avenues for advancing leukemia treatment.</p>","PeriodicalId":19000,"journal":{"name":"Molecular Cancer","volume":"23 1","pages":"240"},"PeriodicalIF":27.7,"publicationDate":"2024-10-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11514791/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142504546","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-10-24DOI: 10.1186/s12943-024-02155-z
Feng Qi, Na Gao, Jia Li, Chenfei Zhou, Jinling Jiang, Bin Zhou, Liting Guo, Xiaohui Feng, Jun Ji, Qu Cai, Liu Yang, Rongjia Zhu, Xinyi Que, Junwei Wu, Wenqi Xi, Wenxing Qin, Jun Zhang
The quest to understand the molecular mechanisms of tumour metastasis and identify pivotal biomarkers for cancer therapy is increasing in importance. Single-omics analyses, constrained by their focus on a single biological layer, cannot fully elucidate the complexities of tumour molecular profiles and can thus overlook crucial molecular targets. In response to this limitation, we developed a multiobjective recommendation system (RJH-Metastasis 1.0) anchored in a multiomics knowledge graph to integrate genome, transcriptome, and proteome data and corroborative literature evidence and then conducted comprehensive analyses of colorectal cancer with liver metastasis (CRCLM). A total of 25 key genes significantly associated with CRCLM were recommended by our system, and GNB1, GATAD2A, GBP2, MACROD1, and EIF5B were further highlighted. Specifically, GNB1 presented fewer mutations but elevated RNA transcription and protein expression in CRCLM patients. The role of GNB1 in promoting the malignant behaviours of colon cancer cells was demonstrated via in vitro and in vivo studies. Aberrant expression of GNB1 could be regulated by METTL1-driven m7G modification. METTL1 knockdown decreased m7G modification in the 3’ UTR of GNB1, increasing its mRNA transcription and translation during liver metastasis. Furthermore, GNB1 induced the formation of an immunosuppressive microenvironment by promoting the CLEC2C-KLRB1 interaction between memory B cells and KLRB1+PD-1+CD8+ cells. GNB1 expression and the efficacy of PD-1 antibody-based treatment in CRCLM patients were significantly correlated. In summary, our recommendation system can be used for effective exploration of key molecules in colorectal cancer, among which GNB1 was identified as a critical CRCLM promoter and immunotherapy biomarker in colorectal cancer patients.
{"title":"A multidimensional recommendation framework for identifying biological targets to aid the diagnosis and treatment of liver metastasis in patients with colorectal cancer","authors":"Feng Qi, Na Gao, Jia Li, Chenfei Zhou, Jinling Jiang, Bin Zhou, Liting Guo, Xiaohui Feng, Jun Ji, Qu Cai, Liu Yang, Rongjia Zhu, Xinyi Que, Junwei Wu, Wenqi Xi, Wenxing Qin, Jun Zhang","doi":"10.1186/s12943-024-02155-z","DOIUrl":"https://doi.org/10.1186/s12943-024-02155-z","url":null,"abstract":"The quest to understand the molecular mechanisms of tumour metastasis and identify pivotal biomarkers for cancer therapy is increasing in importance. Single-omics analyses, constrained by their focus on a single biological layer, cannot fully elucidate the complexities of tumour molecular profiles and can thus overlook crucial molecular targets. In response to this limitation, we developed a multiobjective recommendation system (RJH-Metastasis 1.0) anchored in a multiomics knowledge graph to integrate genome, transcriptome, and proteome data and corroborative literature evidence and then conducted comprehensive analyses of colorectal cancer with liver metastasis (CRCLM). A total of 25 key genes significantly associated with CRCLM were recommended by our system, and GNB1, GATAD2A, GBP2, MACROD1, and EIF5B were further highlighted. Specifically, GNB1 presented fewer mutations but elevated RNA transcription and protein expression in CRCLM patients. The role of GNB1 in promoting the malignant behaviours of colon cancer cells was demonstrated via in vitro and in vivo studies. Aberrant expression of GNB1 could be regulated by METTL1-driven m7G modification. METTL1 knockdown decreased m7G modification in the 3’ UTR of GNB1, increasing its mRNA transcription and translation during liver metastasis. Furthermore, GNB1 induced the formation of an immunosuppressive microenvironment by promoting the CLEC2C-KLRB1 interaction between memory B cells and KLRB1+PD-1+CD8+ cells. GNB1 expression and the efficacy of PD-1 antibody-based treatment in CRCLM patients were significantly correlated. In summary, our recommendation system can be used for effective exploration of key molecules in colorectal cancer, among which GNB1 was identified as a critical CRCLM promoter and immunotherapy biomarker in colorectal cancer patients.","PeriodicalId":19000,"journal":{"name":"Molecular Cancer","volume":"90 1","pages":""},"PeriodicalIF":37.3,"publicationDate":"2024-10-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142488734","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Gastrointestinal (GI) cancers represent a significant health burden worldwide. Their incidence continues to increase, and their management remains a clinical challenge. Chimeric antigen receptor (CAR) natural killer (NK) cells have emerged as a promising alternative to CAR-T cells for immunotherapy of GI cancers. Notably, CAR-NK cells offer several advantages, including reduced risk of graft-versus-host disease, lower cytokine release syndrome, and the ability to target cancer cells through both CAR-dependent and natural cytotoxic mechanisms. This review comprehensively discusses the development and applications of CAR-NK cells in the treatment of GI cancers. We explored various sources of NK cells, CAR design strategies, and the current state of CAR-NK cell therapy for GI cancers, highlighting recent preclinical and clinical trials. Additionally, we addressed existing challenges and propose potential strategies to enhance the efficacy and safety of CAR-NK cell therapy. Our findings highlight the potential of CAR-NK cells to revolutionize GI cancer treatment and pave the way for future clinical applications.
胃肠道（GI）癌症是全球范围内的重大健康负担。其发病率持续上升，其治疗仍然是一项临床挑战。嵌合抗原受体（CAR）自然杀伤（NK）细胞已成为CAR-T细胞免疫治疗消化道癌症的理想替代品。值得注意的是，CAR-NK 细胞具有多种优势，包括降低移植物抗宿主疾病的风险、降低细胞因子释放综合征，以及通过 CAR 依赖性和天然细胞毒性机制靶向癌细胞的能力。本综述全面讨论了 CAR-NK 细胞在消化道癌症治疗中的开发和应用。我们探讨了 NK 细胞的各种来源、CAR 设计策略以及 CAR-NK 细胞治疗消化道癌症的现状，重点介绍了最近的临床前和临床试验。此外，我们还探讨了现有的挑战，并提出了提高 CAR-NK 细胞疗法疗效和安全性的潜在策略。我们的研究结果凸显了 CAR-NK 细胞彻底改变消化道癌症治疗的潜力，并为未来的临床应用铺平了道路。
{"title":"CAR-NK cells for gastrointestinal cancer immunotherapy: from bench to bedside","authors":"Xingwang Zhu, Jieyun Xue, Hongzhou Jiang, Dongwei Xue","doi":"10.1186/s12943-024-02151-3","DOIUrl":"https://doi.org/10.1186/s12943-024-02151-3","url":null,"abstract":"Gastrointestinal (GI) cancers represent a significant health burden worldwide. Their incidence continues to increase, and their management remains a clinical challenge. Chimeric antigen receptor (CAR) natural killer (NK) cells have emerged as a promising alternative to CAR-T cells for immunotherapy of GI cancers. Notably, CAR-NK cells offer several advantages, including reduced risk of graft-versus-host disease, lower cytokine release syndrome, and the ability to target cancer cells through both CAR-dependent and natural cytotoxic mechanisms. This review comprehensively discusses the development and applications of CAR-NK cells in the treatment of GI cancers. We explored various sources of NK cells, CAR design strategies, and the current state of CAR-NK cell therapy for GI cancers, highlighting recent preclinical and clinical trials. Additionally, we addressed existing challenges and propose potential strategies to enhance the efficacy and safety of CAR-NK cell therapy. Our findings highlight the potential of CAR-NK cells to revolutionize GI cancer treatment and pave the way for future clinical applications.","PeriodicalId":19000,"journal":{"name":"Molecular Cancer","volume":"42 1","pages":""},"PeriodicalIF":37.3,"publicationDate":"2024-10-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142487523","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-10-23DOI: 10.1186/s12943-024-02118-4
Akram Ghantous, Semira Gonseth Nusslé, Farah J. Nassar, Natalia Spitz, Alexei Novoloaca, Olga Krali, Eric Nickels, Vincent Cahais, Cyrille Cuenin, Ritu Roy, Shaobo Li, Maxime Caron, Dilys Lam, Peter Daniel Fransquet, John Casement, Gordon Strathdee, Mark S. Pearce, Helen M. Hansen, Hwi-Ho Lee, Yong Sun Lee, Adam J. de Smith, Daniel Sinnett, Siri Eldevik Håberg, Jill A. McKay, Jessica Nordlund, Per Magnus, Terence Dwyer, Richard Saffery, Joseph Leo Wiemels, Monica Cheng Munthe-Kaas, Zdenko Herceg
Cancer is the leading cause of disease-related mortality in children. Causes of leukemia, the most common form, are largely unknown. Growing evidence points to an origin in-utero, when global redistribution of DNA methylation occurs driving tissue differentiation. Epigenome-wide DNA methylation was profiled in surrogate (blood) and target (bone marrow) tissues at birth, diagnosis, remission and relapse of pediatric pre-B acute lymphoblastic leukemia (pre-B ALL) patients. Double-blinded analyses was performed between prospective cohorts extending from birth to diagnosis and retrospective studies backtracking from clinical disease to birth. Validation was carried out using independent technologies and populations. The imprinted and immuno-modulating VTRNA2-1 was hypermethylated (FDR<0.05) at birth in nested cases relative to controls in all tested populations (totaling 317 cases and 483 controls), including European and Hispanic ancestries. VTRNA2-1 methylation was stable over follow-up years after birth and across surrogate, target and other tissues (n=5,023 tissues; 30 types). When profiled in leukemic tissues from two clinical cohorts (totaling 644 cases), VTRNA2-1 methylation exhibited higher levels at diagnosis relative to controls, it reset back to normal levels at remission, and then re-increased to above control levels at relapse. Hypermethylation was significantly associated with worse pre-B ALL patient survival and with reduced VTRNA2-1 expression (n=2,294 tissues; 26 types), supporting a functional and translational role for VTRNA2-1 methylation. This study provides proof-of-concept to detect at birth epigenetic precursors of pediatric pre-B ALL. These alterations were reproducible with different technologies, in three continents and in two ethnicities, and can offer biomarkers for early detection and prognosis as well as actionable targets for therapy. • Precursors of pediatric acute lymphoblastic leukemia may be of epigenetic origin, detectable since birth and affecting patient prognosis. • These epigenetic precursors can be robust over several years and across several populations, ethnicities and surrogate and target tissues.
癌症是儿童因病死亡的主要原因。白血病是最常见的一种癌症，其病因大多不明。越来越多的证据表明，白血病起源于胎儿时期，当时 DNA 甲基化发生了全球性的重新分布，推动了组织分化。研究人员对小儿前 B 型急性淋巴细胞白血病（pre-B ALL）患者出生、诊断、缓解和复发时的替代组织（血液）和目标组织（骨髓）进行了表观遗传组 DNA 甲基化分析。对从出生到诊断的前瞻性队列和从临床疾病到出生的回顾性研究进行了双盲分析。利用独立的技术和人群进行了验证。在所有受试人群（共 317 例病例和 483 例对照）（包括欧洲和西班牙血统）中，嵌套病例与对照组相比，出生时印迹和免疫调节 VTRNA2-1 甲基化水平过高（FDR<0.05）。VTRNA2-1甲基化在出生后数年的随访中保持稳定，在代用组织、靶组织和其他组织中也保持稳定（n=5,023个组织；30种类型）。在对两个临床队列（共 644 例）的白血病组织进行分析时，诊断时 VTRNA2-1 甲基化水平高于对照组，缓解时恢复到正常水平，复发时又重新升高到对照组水平以上。高甲基化与B ALL前期患者存活率降低和VTRNA2-1表达减少有明显相关性（n=2,294个组织；26种类型），支持VTRNA2-1甲基化的功能和转化作用。这项研究为检测小儿先天性B ALL的出生表观遗传前体提供了概念验证。这些改变可通过不同的技术在三大洲和两个种族中重现，可为早期检测和预后提供生物标志物，并为治疗提供可操作的靶点。- 小儿急性淋巴细胞白血病的前体可能源于表观遗传，从出生时就可检测到，并影响患者的预后。- 这些表观遗传前体可在数年内保持稳定，并跨越多个人群、种族、替代组织和靶组织。
{"title":"Epigenome-wide analysis across the development span of pediatric acute lymphoblastic leukemia: backtracking to birth","authors":"Akram Ghantous, Semira Gonseth Nusslé, Farah J. Nassar, Natalia Spitz, Alexei Novoloaca, Olga Krali, Eric Nickels, Vincent Cahais, Cyrille Cuenin, Ritu Roy, Shaobo Li, Maxime Caron, Dilys Lam, Peter Daniel Fransquet, John Casement, Gordon Strathdee, Mark S. Pearce, Helen M. Hansen, Hwi-Ho Lee, Yong Sun Lee, Adam J. de Smith, Daniel Sinnett, Siri Eldevik Håberg, Jill A. McKay, Jessica Nordlund, Per Magnus, Terence Dwyer, Richard Saffery, Joseph Leo Wiemels, Monica Cheng Munthe-Kaas, Zdenko Herceg","doi":"10.1186/s12943-024-02118-4","DOIUrl":"https://doi.org/10.1186/s12943-024-02118-4","url":null,"abstract":"Cancer is the leading cause of disease-related mortality in children. Causes of leukemia, the most common form, are largely unknown. Growing evidence points to an origin in-utero, when global redistribution of DNA methylation occurs driving tissue differentiation. Epigenome-wide DNA methylation was profiled in surrogate (blood) and target (bone marrow) tissues at birth, diagnosis, remission and relapse of pediatric pre-B acute lymphoblastic leukemia (pre-B ALL) patients. Double-blinded analyses was performed between prospective cohorts extending from birth to diagnosis and retrospective studies backtracking from clinical disease to birth. Validation was carried out using independent technologies and populations. The imprinted and immuno-modulating VTRNA2-1 was hypermethylated (FDR<0.05) at birth in nested cases relative to controls in all tested populations (totaling 317 cases and 483 controls), including European and Hispanic ancestries. VTRNA2-1 methylation was stable over follow-up years after birth and across surrogate, target and other tissues (n=5,023 tissues; 30 types). When profiled in leukemic tissues from two clinical cohorts (totaling 644 cases), VTRNA2-1 methylation exhibited higher levels at diagnosis relative to controls, it reset back to normal levels at remission, and then re-increased to above control levels at relapse. Hypermethylation was significantly associated with worse pre-B ALL patient survival and with reduced VTRNA2-1 expression (n=2,294 tissues; 26 types), supporting a functional and translational role for VTRNA2-1 methylation. This study provides proof-of-concept to detect at birth epigenetic precursors of pediatric pre-B ALL. These alterations were reproducible with different technologies, in three continents and in two ethnicities, and can offer biomarkers for early detection and prognosis as well as actionable targets for therapy. • Precursors of pediatric acute lymphoblastic leukemia may be of epigenetic origin, detectable since birth and affecting patient prognosis. • These epigenetic precursors can be robust over several years and across several populations, ethnicities and surrogate and target tissues.","PeriodicalId":19000,"journal":{"name":"Molecular Cancer","volume":"31 1","pages":""},"PeriodicalIF":37.3,"publicationDate":"2024-10-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142488736","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Enhancing the efficacy of CD19 CAR-T cell therapy can significantly improve patient outcomes by reducing relapse rates in CD19 + B cell malignancies. Exogenous or transgenic cytokines are often used to boost the expansion and durability of CAR-T cells but pose risks of severe toxicities. A promising approach to address these limitations is to immobilize cytokines on the surface of CAR-T cells using transmembrane (TM) anchor domains. Given IL-7 can enhance T-cell proliferation and antitumor activity, our study developed membrane-bound IL-7 constructs using different TM anchor domains (CD8, CD28 and B7-1). We primarily found that the CD8 TM provided superior anchoring for IL-7 compared to CD28 and B7-1. Moreover, the IL-7 construct with a CD8 TM (IL7/CD8) enhanced naïve T cell proliferation and effector functions, and improved the in vitro and in vivo antitumor activity of CD19 CAR-T cells. Importantly, although IL7/CD8 could promote T-cell proliferation, it did not sustain long-term autonomous expansion, which could ensure the safety of CD19 CAR-T cells expressing IL7/CD8 in clinical applications. Collectively, the IL7/CD8 construct represents a promising strategy for enhancing the therapeutic potential of CD19 CAR-T cell therapy.
{"title":"Membrane-bound IL-7 immobilized by the CD8 transmembrane region improves efficacy of CD19 CAR-T cell therapy","authors":"Chaoting Zhang, Ting Liu, Shance Li, Xia Teng, Yuge Zhu, Guanyu Zhang, Huimin Xie, Kang Sun, Jiaxin Tu, Wenjun Yang, Zheming Lu","doi":"10.1186/s12943-024-02154-0","DOIUrl":"https://doi.org/10.1186/s12943-024-02154-0","url":null,"abstract":"Enhancing the efficacy of CD19 CAR-T cell therapy can significantly improve patient outcomes by reducing relapse rates in CD19 + B cell malignancies. Exogenous or transgenic cytokines are often used to boost the expansion and durability of CAR-T cells but pose risks of severe toxicities. A promising approach to address these limitations is to immobilize cytokines on the surface of CAR-T cells using transmembrane (TM) anchor domains. Given IL-7 can enhance T-cell proliferation and antitumor activity, our study developed membrane-bound IL-7 constructs using different TM anchor domains (CD8, CD28 and B7-1). We primarily found that the CD8 TM provided superior anchoring for IL-7 compared to CD28 and B7-1. Moreover, the IL-7 construct with a CD8 TM (IL7/CD8) enhanced naïve T cell proliferation and effector functions, and improved the in vitro and in vivo antitumor activity of CD19 CAR-T cells. Importantly, although IL7/CD8 could promote T-cell proliferation, it did not sustain long-term autonomous expansion, which could ensure the safety of CD19 CAR-T cells expressing IL7/CD8 in clinical applications. Collectively, the IL7/CD8 construct represents a promising strategy for enhancing the therapeutic potential of CD19 CAR-T cell therapy.","PeriodicalId":19000,"journal":{"name":"Molecular Cancer","volume":"67 1","pages":""},"PeriodicalIF":37.3,"publicationDate":"2024-10-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142487528","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-10-21DOI: 10.1186/s12943-024-02094-9
Simone Anfossi, Faezeh Darbaniyan, Joseph Quinlan, Steliana Calin, Masayoshi Shimizu, Meng Chen, Paola Rausseo, Michael Winters, Elena Bogatenkova, Kim-Anh Do, Ivan Martinez, Ziyi Li, Loredana Antal, Tudor Rares Olariu, Ignacio Wistuba, George A. Calin
Cancer patients are more susceptible to an aggressive course of COVID-19. Developing biomarkers identifying cancer patients at high risk of COVID-19-related death could help determine who needs early clinical intervention. The miRNAs hosted in the genomic regions associated with the risk of aggressive COVID-19 could represent potential biomarkers for clinical outcomes. Plasma samples were collected at The University of Texas MD Anderson Cancer Center from cancer patients (N = 128) affected by COVID-19. Serum samples were collected from vaccinated healthy individuals (n = 23) at the Municipal Clinical Emergency Teaching Hospital in Timisoara, Romania. An in silico positional cloning approach was used to identify the presence of miRNAs at COVID-19 risk-associated genomic regions: CORSAIRs (COvid-19 RiSk AssocIated genomic Regions). The miRNA levels were measured by RT-qPCR. We found that miRNAs were enriched in CORSAIR. Low plasma levels of hsa-miR-150-5p and hsa-miR-93-5p were associated with higher COVID-19-related death. The levels of hsa-miR-92b-3p were associated with SARS-CoV-2 test positivity. Peripheral blood mononuclear cells (PBMC) increased secretion of hsa-miR-150-5p, hsa-miR-93-5p, and hsa-miR-92b-3p after in vitro TLR7/8- and T cell receptor (TCR)-mediated activation. Increased levels of these three miRNAs were measured in the serum samples of healthy individuals between one and nine months after the second dose of the Pfizer-BioNTech COVID-19 vaccine. SARS-CoV-2 infection of human airway epithelial cells influenced the miRNA levels inside their secreted extracellular vesicles. MiRNAs are enriched at CORSAIR. Plasma miRNA levels can represent a potential blood biomarker for predicting COVID-19-related death in cancer patients.
{"title":"MicroRNAs are enriched at COVID-19 genomic risk regions, and their blood levels correlate with the COVID-19 prognosis of cancer patients infected by SARS-CoV-2","authors":"Simone Anfossi, Faezeh Darbaniyan, Joseph Quinlan, Steliana Calin, Masayoshi Shimizu, Meng Chen, Paola Rausseo, Michael Winters, Elena Bogatenkova, Kim-Anh Do, Ivan Martinez, Ziyi Li, Loredana Antal, Tudor Rares Olariu, Ignacio Wistuba, George A. Calin","doi":"10.1186/s12943-024-02094-9","DOIUrl":"https://doi.org/10.1186/s12943-024-02094-9","url":null,"abstract":"Cancer patients are more susceptible to an aggressive course of COVID-19. Developing biomarkers identifying cancer patients at high risk of COVID-19-related death could help determine who needs early clinical intervention. The miRNAs hosted in the genomic regions associated with the risk of aggressive COVID-19 could represent potential biomarkers for clinical outcomes. Plasma samples were collected at The University of Texas MD Anderson Cancer Center from cancer patients (N = 128) affected by COVID-19. Serum samples were collected from vaccinated healthy individuals (n = 23) at the Municipal Clinical Emergency Teaching Hospital in Timisoara, Romania. An in silico positional cloning approach was used to identify the presence of miRNAs at COVID-19 risk-associated genomic regions: CORSAIRs (COvid-19 RiSk AssocIated genomic Regions). The miRNA levels were measured by RT-qPCR. We found that miRNAs were enriched in CORSAIR. Low plasma levels of hsa-miR-150-5p and hsa-miR-93-5p were associated with higher COVID-19-related death. The levels of hsa-miR-92b-3p were associated with SARS-CoV-2 test positivity. Peripheral blood mononuclear cells (PBMC) increased secretion of hsa-miR-150-5p, hsa-miR-93-5p, and hsa-miR-92b-3p after in vitro TLR7/8- and T cell receptor (TCR)-mediated activation. Increased levels of these three miRNAs were measured in the serum samples of healthy individuals between one and nine months after the second dose of the Pfizer-BioNTech COVID-19 vaccine. SARS-CoV-2 infection of human airway epithelial cells influenced the miRNA levels inside their secreted extracellular vesicles. MiRNAs are enriched at CORSAIR. Plasma miRNA levels can represent a potential blood biomarker for predicting COVID-19-related death in cancer patients.","PeriodicalId":19000,"journal":{"name":"Molecular Cancer","volume":"20 1","pages":""},"PeriodicalIF":37.3,"publicationDate":"2024-10-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142452072","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-10-19DOI: 10.1186/s12943-024-02142-4
Shigao Huang, Min Xu, Xiaojun Deng, Qingyue Da, Miaomiao Li, Hao Huang, Lina Zhao, Linlin Jing, Haibo Wang
Normal tissue and immune organ protection are critical parts of the tumor radiation therapy process. Radiation-induced immune organ damage (RIOD) causes several side reactions by increasing oxidative stress and inflammatory responses, resulting in unsatisfactory curability in tumor radiation therapy. The aim of this study was to develop a novel and efficient anti irradiation nanoparticle and explore its mechanism of protecting splenic tissue from radiation in mice. Nanoparticles of triphenylphosphine cation NIT radicals (NPs-TPP-NIT) were prepared and used to protect the spleens of mice irradiated with X-rays. Splenic tissue histopathology and hematological parameters were investigated to evaluate the protective effect of NPs-TPP-NIT against X-ray radiation. Proteomics was used to identify differentially expressed proteins related to inflammatory factor regulation. In addition, in vitro and in vivo experiments were performed to assess the impact of NPs-TPP-NIT on radiation therapy. NPs-TPP-NIT increased superoxide dismutase, catalase, and glutathione peroxidase activity and decreased malondialdehyde levels and reactive oxygen species generation in the spleens of mice after exposure to 6.0 Gy X-ray radiation. Moreover, NPs-TPP-NIT inhibited cell apoptosis, blocked the activation of cleaved cysteine aspartic acid–specific protease/proteinase, upregulated the expression of Bcl-2, and downregulated that of Bax. We confirmed that NPs-TPP-NIT prevented the IKK/IκB/NF-κB activation induced by ionizing radiation, thereby alleviating radiation-induced splenic inflammatory damage. In addition, when used during radiotherapy for tumors in mice, NPs-TPP-NIT exhibited no significant toxicity and conferred no significant tumor protective effects. NPs-TPP-NIT prevented activation of IKK/IκB/NF-κB signaling, reduced secretion of pro-inflammatory factors, and promoted production of anti-inflammatory factors in the spleen, which exhibited radiation-induced damage repair capability without diminishing the therapeutic effect of radiation therapy. It suggests that NPs-TPP-NIT serve as a potential radioprotective drug to shelter immune organs from radiation-induced damage.
正常组织和免疫器官保护是肿瘤放射治疗过程的关键部分。辐射诱导的免疫器官损伤（RIOD）通过增加氧化应激和炎症反应引起多种副反应，导致肿瘤放射治疗的治愈率不理想。本研究旨在开发一种新型高效的抗辐照纳米粒子，并探索其保护小鼠脾脏组织免受辐射的机制。制备了三苯基膦阳离子 NIT 自由基纳米粒子（NPs-TPP-NIT），并用于保护接受 X 射线照射的小鼠脾脏。研究了脾组织病理学和血液学参数，以评估 NPs-TPP-NIT 对 X 射线辐射的保护作用。蛋白质组学用于鉴定与炎症因子调节相关的差异表达蛋白。此外，还进行了体外和体内实验，以评估 NPs-TPP-NIT 对放射治疗的影响。经 6.0 Gy X 射线照射后，NPs-TPP-NIT 提高了小鼠脾脏中超氧化物歧化酶、过氧化氢酶和谷胱甘肽过氧化物酶的活性，降低了丙二醛水平和活性氧的生成。此外，NPs-TPP-NIT 还能抑制细胞凋亡，阻断半胱氨酸天冬氨酸特异性蛋白酶/蛋白酶的活化，上调 Bcl-2 的表达，下调 Bax 的表达。我们证实，NPs-TPP-NIT 能阻止电离辐射诱导的 IKK/IκB/NF-κB 激活，从而减轻辐射诱导的脾脏炎症损伤。此外，在对小鼠进行肿瘤放疗时，NPs-TPP-NIT 没有表现出明显的毒性，也没有显著的肿瘤保护作用。NPs-TPP-NIT 阻止了 IKK/IκB/NF-κB 信号的活化，减少了促炎因子的分泌，促进了脾脏中抗炎因子的产生，显示了放疗引起的损伤修复能力，而不会降低放疗的治疗效果。这表明，NPs-TPP-NIT 可作为一种潜在的辐射防护药物，保护免疫器官免受辐射损伤。
{"title":"Anti irradiation nanoparticles shelter immune organ from radio-damage via preventing the IKK/IκB/NF-κB activation","authors":"Shigao Huang, Min Xu, Xiaojun Deng, Qingyue Da, Miaomiao Li, Hao Huang, Lina Zhao, Linlin Jing, Haibo Wang","doi":"10.1186/s12943-024-02142-4","DOIUrl":"https://doi.org/10.1186/s12943-024-02142-4","url":null,"abstract":"Normal tissue and immune organ protection are critical parts of the tumor radiation therapy process. Radiation-induced immune organ damage (RIOD) causes several side reactions by increasing oxidative stress and inflammatory responses, resulting in unsatisfactory curability in tumor radiation therapy. The aim of this study was to develop a novel and efficient anti irradiation nanoparticle and explore its mechanism of protecting splenic tissue from radiation in mice. Nanoparticles of triphenylphosphine cation NIT radicals (NPs-TPP-NIT) were prepared and used to protect the spleens of mice irradiated with X-rays. Splenic tissue histopathology and hematological parameters were investigated to evaluate the protective effect of NPs-TPP-NIT against X-ray radiation. Proteomics was used to identify differentially expressed proteins related to inflammatory factor regulation. In addition, in vitro and in vivo experiments were performed to assess the impact of NPs-TPP-NIT on radiation therapy. NPs-TPP-NIT increased superoxide dismutase, catalase, and glutathione peroxidase activity and decreased malondialdehyde levels and reactive oxygen species generation in the spleens of mice after exposure to 6.0 Gy X-ray radiation. Moreover, NPs-TPP-NIT inhibited cell apoptosis, blocked the activation of cleaved cysteine aspartic acid–specific protease/proteinase, upregulated the expression of Bcl-2, and downregulated that of Bax. We confirmed that NPs-TPP-NIT prevented the IKK/IκB/NF-κB activation induced by ionizing radiation, thereby alleviating radiation-induced splenic inflammatory damage. In addition, when used during radiotherapy for tumors in mice, NPs-TPP-NIT exhibited no significant toxicity and conferred no significant tumor protective effects. NPs-TPP-NIT prevented activation of IKK/IκB/NF-κB signaling, reduced secretion of pro-inflammatory factors, and promoted production of anti-inflammatory factors in the spleen, which exhibited radiation-induced damage repair capability without diminishing the therapeutic effect of radiation therapy. It suggests that NPs-TPP-NIT serve as a potential radioprotective drug to shelter immune organs from radiation-induced damage.","PeriodicalId":19000,"journal":{"name":"Molecular Cancer","volume":"23 1","pages":""},"PeriodicalIF":37.3,"publicationDate":"2024-10-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142449859","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
R-loops are three-stranded nucleic acid structures composed of an RNA–DNA hybrid and a displaced DNA strand. They are widespread and play crucial roles in regulating gene expression, DNA replication, and DNA and histone modifications. However, their regulatory mechanisms remain unclear. As R-loop detection technology advances, changes in R-loop levels have been observed in cancer models, often associated with transcription-replication conflicts and genomic instability. N6-methyladenosine (m6A) is an RNA epigenetic modification that regulates gene expression by affecting RNA localization, splicing, translation, and degradation. Upon reviewing the literature, we found that R-loops with m6A modifications are implicated in tumor development and progression. This article summarizes the molecular mechanisms and detection methods of R-loops and m6A modifications in gene regulation, and reviews recent research on m6A-modified R-loops in oncology. Our goal is to provide new insights into the origins of genomic instability in cancer and potential strategies for targeted therapy.
R 环是一种三链核酸结构，由一条 RNA-DNA 杂交链和一条移位的 DNA 链组成。它们广泛存在，在调控基因表达、DNA 复制以及 DNA 和组蛋白修饰方面发挥着重要作用。然而，它们的调控机制仍不清楚。随着 R 环检测技术的发展，在癌症模型中观察到了 R 环水平的变化，这种变化往往与转录复制冲突和基因组不稳定性有关。N6-甲基腺苷（m6A）是一种 RNA 表观遗传修饰，通过影响 RNA 定位、剪接、翻译和降解来调控基因表达。通过查阅文献，我们发现带有 m6A 修饰的 R 环与肿瘤的发生和发展有关。本文总结了 R 环和 m6A 修饰在基因调控中的分子机制和检测方法，并回顾了肿瘤学中有关 m6A 修饰 R 环的最新研究。我们的目标是为癌症基因组不稳定性的起源和潜在的靶向治疗策略提供新的见解。
{"title":"R-loops’ m6A modification and its roles in cancers","authors":"Yue Qiu, Changfeng Man, Luyu Zhu, Shiqi Zhang, Xiaoyan Wang, Dandan Gong, Yu Fan","doi":"10.1186/s12943-024-02148-y","DOIUrl":"https://doi.org/10.1186/s12943-024-02148-y","url":null,"abstract":"R-loops are three-stranded nucleic acid structures composed of an RNA–DNA hybrid and a displaced DNA strand. They are widespread and play crucial roles in regulating gene expression, DNA replication, and DNA and histone modifications. However, their regulatory mechanisms remain unclear. As R-loop detection technology advances, changes in R-loop levels have been observed in cancer models, often associated with transcription-replication conflicts and genomic instability. N6-methyladenosine (m6A) is an RNA epigenetic modification that regulates gene expression by affecting RNA localization, splicing, translation, and degradation. Upon reviewing the literature, we found that R-loops with m6A modifications are implicated in tumor development and progression. This article summarizes the molecular mechanisms and detection methods of R-loops and m6A modifications in gene regulation, and reviews recent research on m6A-modified R-loops in oncology. Our goal is to provide new insights into the origins of genomic instability in cancer and potential strategies for targeted therapy.","PeriodicalId":19000,"journal":{"name":"Molecular Cancer","volume":"5 1","pages":""},"PeriodicalIF":37.3,"publicationDate":"2024-10-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142448581","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
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