Drug resistance is a common challenge in clinical tumor treatment. A reduction in drug sensitivity of tumor cells is often accompanied by an increase in autophagy levels, leading to autophagy-related resistance. The effectiveness of combining chemotherapy drugs with autophagy inducers/inhibitors has been widely confirmed, but the mechanisms are still unclear. Ferroptosis and pyroptosis can be affected by various types of autophagy. Therefore, ferroptosis and pyroptosis have crosstalk via autophagy, potentially leading to a switch in cell death types under certain conditions. As two forms of inflammatory programmed cell death, ferroptosis and pyroptosis have different effects on inflammation, and the cGAS-STING signaling pathway is also involved. Therefore, it also plays an important role in the progression of some chronic inflammatory diseases. This review discusses the relationship between autophagy, ferroptosis and pyroptosis, and attempts to uncover the reasons behind the evasion of tumor cell death and the nature of drug resistance.
{"title":"Ferroptosis and pyroptosis are connected through autophagy: a new perspective of overcoming drug resistance","authors":"Peng Zhao, Shuangshuang Yin, Yuling Qiu, Changgang Sun, Haiyang Yu","doi":"10.1186/s12943-024-02217-2","DOIUrl":"https://doi.org/10.1186/s12943-024-02217-2","url":null,"abstract":"Drug resistance is a common challenge in clinical tumor treatment. A reduction in drug sensitivity of tumor cells is often accompanied by an increase in autophagy levels, leading to autophagy-related resistance. The effectiveness of combining chemotherapy drugs with autophagy inducers/inhibitors has been widely confirmed, but the mechanisms are still unclear. Ferroptosis and pyroptosis can be affected by various types of autophagy. Therefore, ferroptosis and pyroptosis have crosstalk via autophagy, potentially leading to a switch in cell death types under certain conditions. As two forms of inflammatory programmed cell death, ferroptosis and pyroptosis have different effects on inflammation, and the cGAS-STING signaling pathway is also involved. Therefore, it also plays an important role in the progression of some chronic inflammatory diseases. This review discusses the relationship between autophagy, ferroptosis and pyroptosis, and attempts to uncover the reasons behind the evasion of tumor cell death and the nature of drug resistance.","PeriodicalId":19000,"journal":{"name":"Molecular Cancer","volume":"45 1","pages":""},"PeriodicalIF":37.3,"publicationDate":"2025-01-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142987429","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 : 2025-01-17DOI: 10.1186/s12943-024-02219-0
Qibo Huang, Bai Hu, Ping Zhang, Ye Yuan, Shiwei Yue, Xiaoping Chen, Junnan Liang, Zhouping Tang, Bixiang Zhang
The study of the multifaceted interactions between neuroscience and cancer is an emerging field with significant implications for understanding tumor biology and the innovation in therapeutic approaches. Increasing evidence suggests that neurological functions are connected with tumorigenesis. In particular, the peripheral and central nervous systems, synapse, neurotransmitters, and neurotrophins affect tumor progression and metastasis through various regulatory approaches and the tumor immune microenvironment. In this review, we summarized the neurological functions that affect tumorigenesis and metastasis, which are controlled by the central and peripheral nervous systems. We also explored the roles of neurotransmitters and neurotrophins in cancer progression. Moreover, we examined the interplay between the nervous system and the tumor immune microenvironment. We have also identified drugs that target the nervous system for cancer treatment. In this review we present the work supporting that therapeutic agent targeting the nervous system could have significant potential to improve cancer therapy.
{"title":"Neuroscience of cancer: unraveling the complex interplay between the nervous system, the tumor and the tumor immune microenvironment","authors":"Qibo Huang, Bai Hu, Ping Zhang, Ye Yuan, Shiwei Yue, Xiaoping Chen, Junnan Liang, Zhouping Tang, Bixiang Zhang","doi":"10.1186/s12943-024-02219-0","DOIUrl":"https://doi.org/10.1186/s12943-024-02219-0","url":null,"abstract":"The study of the multifaceted interactions between neuroscience and cancer is an emerging field with significant implications for understanding tumor biology and the innovation in therapeutic approaches. Increasing evidence suggests that neurological functions are connected with tumorigenesis. In particular, the peripheral and central nervous systems, synapse, neurotransmitters, and neurotrophins affect tumor progression and metastasis through various regulatory approaches and the tumor immune microenvironment. In this review, we summarized the neurological functions that affect tumorigenesis and metastasis, which are controlled by the central and peripheral nervous systems. We also explored the roles of neurotransmitters and neurotrophins in cancer progression. Moreover, we examined the interplay between the nervous system and the tumor immune microenvironment. We have also identified drugs that target the nervous system for cancer treatment. In this review we present the work supporting that therapeutic agent targeting the nervous system could have significant potential to improve cancer therapy.","PeriodicalId":19000,"journal":{"name":"Molecular Cancer","volume":"30 1","pages":""},"PeriodicalIF":37.3,"publicationDate":"2025-01-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142987427","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 : 2025-01-16DOI: 10.1186/s12943-024-02221-6
Sophia Daum, Lilith Decristoforo, Mira Mousa, Stefan Salcher, Christina Plattner, Baharak Hosseinkhani, Zlatko Trajanoski, Dominik Wolf, Peter Carmeliet, Andreas Pircher
The dynamic interactions between tumor endothelial cells (TECs) and the immune microenvironment play a critical role in the progression of non-small cell lung cancer (NSCLC). In general, endothelial cells exhibit diverse immunomodulatory properties, influencing immune cell recruitment, antigen presentation, and regulation of immune checkpoint expression. Understanding the multifaceted roles of TECs as well as assigning specific functional hallmarks to various TEC phenotypes offer new avenues for targeted development of therapeutic interventions, particularly in the context of advanced immunotherapy and anti-angiogenic treatments. This review provides insights into the complex interplay between TECs and the immune system in NSCLC including discussion of potential optimized therapeutic opportunities.
{"title":"Unveiling the immunomodulatory dance: endothelial cells’ function and their role in non-small cell lung cancer","authors":"Sophia Daum, Lilith Decristoforo, Mira Mousa, Stefan Salcher, Christina Plattner, Baharak Hosseinkhani, Zlatko Trajanoski, Dominik Wolf, Peter Carmeliet, Andreas Pircher","doi":"10.1186/s12943-024-02221-6","DOIUrl":"https://doi.org/10.1186/s12943-024-02221-6","url":null,"abstract":"The dynamic interactions between tumor endothelial cells (TECs) and the immune microenvironment play a critical role in the progression of non-small cell lung cancer (NSCLC). In general, endothelial cells exhibit diverse immunomodulatory properties, influencing immune cell recruitment, antigen presentation, and regulation of immune checkpoint expression. Understanding the multifaceted roles of TECs as well as assigning specific functional hallmarks to various TEC phenotypes offer new avenues for targeted development of therapeutic interventions, particularly in the context of advanced immunotherapy and anti-angiogenic treatments. This review provides insights into the complex interplay between TECs and the immune system in NSCLC including discussion of potential optimized therapeutic opportunities.","PeriodicalId":19000,"journal":{"name":"Molecular Cancer","volume":"24 1","pages":""},"PeriodicalIF":37.3,"publicationDate":"2025-01-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142986788","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 : 2025-01-16DOI: 10.1186/s12943-025-02228-7
Haoxin Luyang, Feng Zeng, Yan Lei, Qian He, Yanhong Zhou, Juan Xu
Neutrophils, traditionally considered as non-specific components of the innate immune system, have garnered considerable research interest due to their dual roles in both promoting and inhibiting tumor progression. This paper seeks to clarify the specific mechanisms by which neutrophils play a bidirectional role in tumor immunity and the factors that influence these roles. By conducting a comprehensive analysis and synthesis of a vast array of relevant literature, it has become evident that neutrophils can influence tumor development and invasive migration through various mechanisms, thereby exerting their anti-tumor effects. Conversely, they can also facilitate tumorigenesis and proliferation, as well as affect the normal physiological functions of other immune cells, thus exerting pro-tumor effects. Moreover, neutrophils are influenced by tumor cells and their unique microenvironment, which in turn affects their heterogeneity and plasticity. Neutrophils interact with tumor cells to regulate various aspects of their life activities precisely. This paper also identifies unresolved issues in the research concerning the bidirectional role of neutrophils in tumorigenesis and tumor development, offering new opportunities and challenges for advancing our understanding. This, in turn, can aid in the proper application of these insights to clinical treatment strategies.
{"title":"Bidirectional role of neutrophils in tumor development","authors":"Haoxin Luyang, Feng Zeng, Yan Lei, Qian He, Yanhong Zhou, Juan Xu","doi":"10.1186/s12943-025-02228-7","DOIUrl":"https://doi.org/10.1186/s12943-025-02228-7","url":null,"abstract":"Neutrophils, traditionally considered as non-specific components of the innate immune system, have garnered considerable research interest due to their dual roles in both promoting and inhibiting tumor progression. This paper seeks to clarify the specific mechanisms by which neutrophils play a bidirectional role in tumor immunity and the factors that influence these roles. By conducting a comprehensive analysis and synthesis of a vast array of relevant literature, it has become evident that neutrophils can influence tumor development and invasive migration through various mechanisms, thereby exerting their anti-tumor effects. Conversely, they can also facilitate tumorigenesis and proliferation, as well as affect the normal physiological functions of other immune cells, thus exerting pro-tumor effects. Moreover, neutrophils are influenced by tumor cells and their unique microenvironment, which in turn affects their heterogeneity and plasticity. Neutrophils interact with tumor cells to regulate various aspects of their life activities precisely. This paper also identifies unresolved issues in the research concerning the bidirectional role of neutrophils in tumorigenesis and tumor development, offering new opportunities and challenges for advancing our understanding. This, in turn, can aid in the proper application of these insights to clinical treatment strategies.","PeriodicalId":19000,"journal":{"name":"Molecular Cancer","volume":"66 1","pages":""},"PeriodicalIF":37.3,"publicationDate":"2025-01-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142986787","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 : 2025-01-15DOI: 10.1186/s12943-025-02227-8
Ting Ding, Chang Liu, Zhengyu Li
The polymorphic microbiome is considered a new hallmark of cancer. Advances in High-Throughput Sequencing have fostered rapid developments in microbiome research. The interaction between cancer cells, immune cells, and microbiota is defined as the immuno-oncology microbiome (IOM) axis. Fungal microbes (the mycobiome), although representing only ∼ 0.1-1% of the microbiome, are a critical immunologically active component of the tumor microbiome. Accumulating evidence suggests a possible involvement of commensal and pathogenic fungi in cancer initiation, progression, and treatment responsiveness. The tumor-associated mycobiome mainly consists of the gut mycobiome, the oral mycobiome, and the intratumoral mycobiome. However, the role of fungi in cancer remains poorly understood, and the diversity and complexity of analytical methods make it challenging to access this field. This review aims to elucidate the causal and complicit roles of mycobiome in cancer development and progression while highlighting the issues that need to be addressed in executing such research. We systematically summarize the advantages and limitations of current fungal detection and analysis methods. We enumerate and integrate these recent findings into our current understanding of the tumor mycobiome, accompanied by the prospect of novel and exhilarating clinical implications.
{"title":"The mycobiome in human cancer: analytical challenges, molecular mechanisms, and therapeutic implications","authors":"Ting Ding, Chang Liu, Zhengyu Li","doi":"10.1186/s12943-025-02227-8","DOIUrl":"https://doi.org/10.1186/s12943-025-02227-8","url":null,"abstract":"The polymorphic microbiome is considered a new hallmark of cancer. Advances in High-Throughput Sequencing have fostered rapid developments in microbiome research. The interaction between cancer cells, immune cells, and microbiota is defined as the immuno-oncology microbiome (IOM) axis. Fungal microbes (the mycobiome), although representing only ∼ 0.1-1% of the microbiome, are a critical immunologically active component of the tumor microbiome. Accumulating evidence suggests a possible involvement of commensal and pathogenic fungi in cancer initiation, progression, and treatment responsiveness. The tumor-associated mycobiome mainly consists of the gut mycobiome, the oral mycobiome, and the intratumoral mycobiome. However, the role of fungi in cancer remains poorly understood, and the diversity and complexity of analytical methods make it challenging to access this field. This review aims to elucidate the causal and complicit roles of mycobiome in cancer development and progression while highlighting the issues that need to be addressed in executing such research. We systematically summarize the advantages and limitations of current fungal detection and analysis methods. We enumerate and integrate these recent findings into our current understanding of the tumor mycobiome, accompanied by the prospect of novel and exhilarating clinical implications.","PeriodicalId":19000,"journal":{"name":"Molecular Cancer","volume":"84 1","pages":""},"PeriodicalIF":37.3,"publicationDate":"2025-01-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142981184","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 : 2025-01-15DOI: 10.1186/s12943-025-02225-w
Lin Zhao, Yajun Gui, Jing Cai, Xiangying Deng
Biometallic ions play a crucial role in regulating the immune system. In recent years, cancer immunotherapy has become a breakthrough in cancer treatment, achieving good efficacy in a wide range of cancers with its specificity and durability advantages. However, existing therapies still face challenges, such as immune tolerance and immune escape. Biometallic ions (e.g. zinc, copper, magnesium, manganese, etc.) can assist in enhancing the efficacy of immunotherapy through the activation of immune cells, enhancement of tumor antigen presentation, and improvement of the tumor microenvironment. In addition, biometallic ions and derivatives can directly inhibit tumor cell progression and offer the possibility of effectively overcoming the limitations of current cancer immunotherapy by promoting immune responses and reducing immunosuppressive signals. This review explores the role and potential application prospects of biometallic ions in cancer immunotherapy, providing new ideas for future clinical application of metal ions as part of cancer immunotherapy and helping to guide the development of more effective and safe therapeutic regimens.
{"title":"Biometallic ions and derivatives: a new direction for cancer immunotherapy","authors":"Lin Zhao, Yajun Gui, Jing Cai, Xiangying Deng","doi":"10.1186/s12943-025-02225-w","DOIUrl":"https://doi.org/10.1186/s12943-025-02225-w","url":null,"abstract":"Biometallic ions play a crucial role in regulating the immune system. In recent years, cancer immunotherapy has become a breakthrough in cancer treatment, achieving good efficacy in a wide range of cancers with its specificity and durability advantages. However, existing therapies still face challenges, such as immune tolerance and immune escape. Biometallic ions (e.g. zinc, copper, magnesium, manganese, etc.) can assist in enhancing the efficacy of immunotherapy through the activation of immune cells, enhancement of tumor antigen presentation, and improvement of the tumor microenvironment. In addition, biometallic ions and derivatives can directly inhibit tumor cell progression and offer the possibility of effectively overcoming the limitations of current cancer immunotherapy by promoting immune responses and reducing immunosuppressive signals. This review explores the role and potential application prospects of biometallic ions in cancer immunotherapy, providing new ideas for future clinical application of metal ions as part of cancer immunotherapy and helping to guide the development of more effective and safe therapeutic regimens.","PeriodicalId":19000,"journal":{"name":"Molecular Cancer","volume":"118 1","pages":""},"PeriodicalIF":37.3,"publicationDate":"2025-01-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142981341","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}
The N6-methyladenosine (m6A) modification serves as an essential epigenetic regulator in eukaryotic cells, playing a significant role in tumorigenesis and cancer progression. However, the detailed biological functions and underlying mechanisms of m6A regulation in gastric cancer (GC) are poorly understood. Our research revealed that the m6A demethylase ALKBH5 was markedly downregulated in GC tissues, which was associated with poor patient prognosis. Functional studies demonstrated that suppressing ALKBH5 expression enhanced GC cell proliferation, migration, and invasion. Mechanistically, ALKBH5 removed m6A modifications from the 5’ uncapped and polyadenylated transcripts (UPTs) of WRAP53. This demethylation decreased WRAP53 stability and translation efficiency. The lower level of WRAP53 disrupts the interaction between USP6 and RALBP1 protein, promoting RALBP1 degradation and thereby suppressing the PI3K/Akt/mTOR signaling cascade, ultimately attenuating the progression of GC. These findings highlight the pivotal role of ALKBH5-mediated m6A demethylation in inhibiting GC progression and the potential role of ALKBH5 as a promising biomarker and therapeutic target for GC intervention.
{"title":"ALKBH5 suppresses gastric cancer tumorigenesis and metastasis by inhibiting the translation of uncapped WRAP53 RNA isoforms in an m6A-dependent manner","authors":"Ziqi Zheng, Feizhi Lin, Baiwei Zhao, Guoming Chen, Chengzhi Wei, Xiaojiang Chen, Runcong Nie, Ruopeng Zhang, Zhoukai Zhao, Zhiwei Zhou, Yuanfang Li, Weigang Dai, Yijia Lin, Yongming Chen","doi":"10.1186/s12943-024-02223-4","DOIUrl":"https://doi.org/10.1186/s12943-024-02223-4","url":null,"abstract":"The N6-methyladenosine (m6A) modification serves as an essential epigenetic regulator in eukaryotic cells, playing a significant role in tumorigenesis and cancer progression. However, the detailed biological functions and underlying mechanisms of m6A regulation in gastric cancer (GC) are poorly understood. Our research revealed that the m6A demethylase ALKBH5 was markedly downregulated in GC tissues, which was associated with poor patient prognosis. Functional studies demonstrated that suppressing ALKBH5 expression enhanced GC cell proliferation, migration, and invasion. Mechanistically, ALKBH5 removed m6A modifications from the 5’ uncapped and polyadenylated transcripts (UPTs) of WRAP53. This demethylation decreased WRAP53 stability and translation efficiency. The lower level of WRAP53 disrupts the interaction between USP6 and RALBP1 protein, promoting RALBP1 degradation and thereby suppressing the PI3K/Akt/mTOR signaling cascade, ultimately attenuating the progression of GC. These findings highlight the pivotal role of ALKBH5-mediated m6A demethylation in inhibiting GC progression and the potential role of ALKBH5 as a promising biomarker and therapeutic target for GC intervention.","PeriodicalId":19000,"journal":{"name":"Molecular Cancer","volume":"74 1","pages":""},"PeriodicalIF":37.3,"publicationDate":"2025-01-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142981183","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 : 2025-01-15DOI: 10.1186/s12943-024-02212-7
Besan H. Alsaafeen, Bassam R. Ali, Eyad Elkord
The last decade has witnessed unprecedented succusses with the use of immune checkpoint inhibitors in treating cancer. Nevertheless, the proportion of patients who respond favorably to the treatment remained rather modest, partially due to treatment resistance. This has fueled a wave of research into potential mechanisms of resistance to immune checkpoint inhibitors which can be classified into primary resistance or acquired resistance after an initial response. In the current review, we summarize what is known so far about the mechanisms of resistance in terms of being tumor-intrinsic or tumor-extrinsic taking into account the multimodal crosstalk between the tumor, immune system compartment and other host-related factors.
{"title":"Resistance mechanisms to immune checkpoint inhibitors: updated insights","authors":"Besan H. Alsaafeen, Bassam R. Ali, Eyad Elkord","doi":"10.1186/s12943-024-02212-7","DOIUrl":"https://doi.org/10.1186/s12943-024-02212-7","url":null,"abstract":"The last decade has witnessed unprecedented succusses with the use of immune checkpoint inhibitors in treating cancer. Nevertheless, the proportion of patients who respond favorably to the treatment remained rather modest, partially due to treatment resistance. This has fueled a wave of research into potential mechanisms of resistance to immune checkpoint inhibitors which can be classified into primary resistance or acquired resistance after an initial response. In the current review, we summarize what is known so far about the mechanisms of resistance in terms of being tumor-intrinsic or tumor-extrinsic taking into account the multimodal crosstalk between the tumor, immune system compartment and other host-related factors.","PeriodicalId":19000,"journal":{"name":"Molecular Cancer","volume":"92 1","pages":""},"PeriodicalIF":37.3,"publicationDate":"2025-01-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142981335","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 : 2025-01-14DOI: 10.1186/s12943-024-02209-2
Domenico Lo Tartaro, Beatrice Aramini, Valentina Masciale, Nikolaos Paschalidis, Francesco Demetrio Lofaro, Anita Neroni, Rebecca Borella, Elena Santacroce, Alin Liviu Ciobanu, Anna Valeria Samarelli, Federica Boraldi, Daniela Quaglino, Alessandra Dubini, Michele Gaudio, Gloria Manzotti, Francesca Reggiani, Federica Torricelli, Alessia Ciarrocchi, Antonino Neri, Federica Bertolini, Massimo Dominici, Pier Luigi Filosso, Franco Stella, Lara Gibellini, Sara De Biasi, Andrea Cossarizza
B cells have emerged as central players in the tumor microenvironment (TME) of non-small cell lung cancer (NSCLC). However, although there is clear evidence for their involvement in cancer immunity, scanty data exist on the characterization of B cell phenotypes, bioenergetic profiles and possible interactions with T cells in the context of NSCLC. In this study, using polychromatic flow cytometry, mass cytometry, and spatial transcriptomics we explored the intricate landscape of B cell phenotypes, bioenergetics, and their interaction with T cells in NSCLC. Our analysis revealed that TME contains diverse B cell clusters, including VISTA+ Bregs, with distinct metabolic and functional profiles. Target liquid chromatography-tandem mass spectrometry confirmed the expression of VISTA on B cells. VISTA+ Bregs displayed high metabolic demand and were able to produce different cytokines, including interleukin (IL)-10, transforming growth factor (TGF)-β, IL-6, tumor necrosis factor (TNF), and granulocyte–macrophage colony-stimulating factor (GM-CSF). Spatial analysis showed colocalization of B cells with CD4+/CD8+ T lymphocytes in TME. The computational analysis of intercellular communications that links ligands to target genes, performed by NicheNet, predicted B-T interactions via VISTA-PSGL-1 axis. Colocalization analyses revealed that PSGL-1 T cells and VISTA+ B cells are adjacent in the TME. Notably, tumor infiltrating CD8+ T cells expressing PSGL-1 exhibited enhanced metabolism and cytotoxicity. In NSCLC patients, prediction analysis performed by PENCIL revealed the presence of an association between PSGL-1+CD8+ T cells and VISTA+ Bregs with lung recurrence. Our findings suggest a potential interaction between Bregs and T cells through the VISTA-PSGL-1 axis, that could influence NSCLC recurrence.
{"title":"Metabolically activated and highly polyfunctional intratumoral VISTA+ regulatory B cells are associated with tumor recurrence in early-stage NSCLC","authors":"Domenico Lo Tartaro, Beatrice Aramini, Valentina Masciale, Nikolaos Paschalidis, Francesco Demetrio Lofaro, Anita Neroni, Rebecca Borella, Elena Santacroce, Alin Liviu Ciobanu, Anna Valeria Samarelli, Federica Boraldi, Daniela Quaglino, Alessandra Dubini, Michele Gaudio, Gloria Manzotti, Francesca Reggiani, Federica Torricelli, Alessia Ciarrocchi, Antonino Neri, Federica Bertolini, Massimo Dominici, Pier Luigi Filosso, Franco Stella, Lara Gibellini, Sara De Biasi, Andrea Cossarizza","doi":"10.1186/s12943-024-02209-2","DOIUrl":"https://doi.org/10.1186/s12943-024-02209-2","url":null,"abstract":"B cells have emerged as central players in the tumor microenvironment (TME) of non-small cell lung cancer (NSCLC). However, although there is clear evidence for their involvement in cancer immunity, scanty data exist on the characterization of B cell phenotypes, bioenergetic profiles and possible interactions with T cells in the context of NSCLC. In this study, using polychromatic flow cytometry, mass cytometry, and spatial transcriptomics we explored the intricate landscape of B cell phenotypes, bioenergetics, and their interaction with T cells in NSCLC. Our analysis revealed that TME contains diverse B cell clusters, including VISTA+ Bregs, with distinct metabolic and functional profiles. Target liquid chromatography-tandem mass spectrometry confirmed the expression of VISTA on B cells. VISTA+ Bregs displayed high metabolic demand and were able to produce different cytokines, including interleukin (IL)-10, transforming growth factor (TGF)-β, IL-6, tumor necrosis factor (TNF), and granulocyte–macrophage colony-stimulating factor (GM-CSF). Spatial analysis showed colocalization of B cells with CD4+/CD8+ T lymphocytes in TME. The computational analysis of intercellular communications that links ligands to target genes, performed by NicheNet, predicted B-T interactions via VISTA-PSGL-1 axis. Colocalization analyses revealed that PSGL-1 T cells and VISTA+ B cells are adjacent in the TME. Notably, tumor infiltrating CD8+ T cells expressing PSGL-1 exhibited enhanced metabolism and cytotoxicity. In NSCLC patients, prediction analysis performed by PENCIL revealed the presence of an association between PSGL-1+CD8+ T cells and VISTA+ Bregs with lung recurrence. Our findings suggest a potential interaction between Bregs and T cells through the VISTA-PSGL-1 axis, that could influence NSCLC recurrence.","PeriodicalId":19000,"journal":{"name":"Molecular Cancer","volume":"15 1","pages":""},"PeriodicalIF":37.3,"publicationDate":"2025-01-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142974780","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 : 2025-01-14DOI: 10.1186/s12943-024-02206-5
Natalia Hermán-Sánchez, Mercedes del Rio-Moreno, Rubén Ciria, Marina E. Sánchez-Frias, Maite G. Fernández-Barrena, Iker Uriarte, Eduardo Chicano-Galvez, Ignacio Ortea, Ángela Peralbo-Molina, Javier Briceño, Matías A. Avila, Manuel Rodríguez-Perálvarez, Raúl M. Luque, Juan L. López-Cánovas, Manuel D. Gahete
Hepatocellular carcinoma (HCC) genetic/transcriptomic signatures have been widely described. However, its proteomic characterization is incomplete. We performed non-targeted quantitative proteomics of HCC samples and explored its clinical, functional, and molecular consequences. Non-targeted quantitative proteomics were performed on cytosolic and nuclear fractions of liver samples [HCC vs. non-tumour adjacent tissue (NTAT), n = 42 patients]. Changes were confirmed in 7 in silico HCC cohorts. Functional and molecular implications were evaluated on HCC-derived cell lines after silencing/overexpressing VARS1 and/or MAGI1. VARS1-overexpressing Hep3B cells were used for in vivo studies [Extreme Limiting Dilution Assay (ELDA) and orthotopic tumour formation]. Quantitative proteomics were performed on VARS1-overexpressing HCC cell lines. Quantitative proteomics revealed the dysregulation of the cytosolic and nuclear proteomes in HCC, and defined two proteomic HCC subgroups, the most aggressive associated to the dysregulation of the aminoacyl-tRNA synthetases (ARSs). ARSs dysregulation was corroborated in in silico HCC cohorts and associated to poor prognosis. Patients with ARSs upregulation had genomic/transcriptomic characteristics of the proliferative HCC. Valine tRNA-aminoacyl synthetase (VARS1) was the ARSs most consistently overexpressed and associated to aggressiveness. VARS1 modulation (silencing/overexpression) altered tumour establishment-associated parameters in vitro and/or in vivo. Quantitative proteomics on cells overexpressing VARS1 and rescue experiments identified the downregulation of MAGI1, a tumour suppressor in HCC, as a mediator of VARS1 function. Quantitative proteomics defines two prognosis-related proteomic HCC subgroups. ARSs machinery is dysregulated in the aggressive subgroup, bearing potential as prognostic biomarkers. VARS1 promotes aggressiveness through the modulation of MAGI1, representing a novel targetable vulnerability in HCC.
{"title":"Quantitative proteomic analysis unveils a critical role of VARS1 in hepatocellular carcinoma aggressiveness through the modulation of MAGI1 expression","authors":"Natalia Hermán-Sánchez, Mercedes del Rio-Moreno, Rubén Ciria, Marina E. Sánchez-Frias, Maite G. Fernández-Barrena, Iker Uriarte, Eduardo Chicano-Galvez, Ignacio Ortea, Ángela Peralbo-Molina, Javier Briceño, Matías A. Avila, Manuel Rodríguez-Perálvarez, Raúl M. Luque, Juan L. López-Cánovas, Manuel D. Gahete","doi":"10.1186/s12943-024-02206-5","DOIUrl":"https://doi.org/10.1186/s12943-024-02206-5","url":null,"abstract":"Hepatocellular carcinoma (HCC) genetic/transcriptomic signatures have been widely described. However, its proteomic characterization is incomplete. We performed non-targeted quantitative proteomics of HCC samples and explored its clinical, functional, and molecular consequences. Non-targeted quantitative proteomics were performed on cytosolic and nuclear fractions of liver samples [HCC vs. non-tumour adjacent tissue (NTAT), n = 42 patients]. Changes were confirmed in 7 in silico HCC cohorts. Functional and molecular implications were evaluated on HCC-derived cell lines after silencing/overexpressing VARS1 and/or MAGI1. VARS1-overexpressing Hep3B cells were used for in vivo studies [Extreme Limiting Dilution Assay (ELDA) and orthotopic tumour formation]. Quantitative proteomics were performed on VARS1-overexpressing HCC cell lines. Quantitative proteomics revealed the dysregulation of the cytosolic and nuclear proteomes in HCC, and defined two proteomic HCC subgroups, the most aggressive associated to the dysregulation of the aminoacyl-tRNA synthetases (ARSs). ARSs dysregulation was corroborated in in silico HCC cohorts and associated to poor prognosis. Patients with ARSs upregulation had genomic/transcriptomic characteristics of the proliferative HCC. Valine tRNA-aminoacyl synthetase (VARS1) was the ARSs most consistently overexpressed and associated to aggressiveness. VARS1 modulation (silencing/overexpression) altered tumour establishment-associated parameters in vitro and/or in vivo. Quantitative proteomics on cells overexpressing VARS1 and rescue experiments identified the downregulation of MAGI1, a tumour suppressor in HCC, as a mediator of VARS1 function. Quantitative proteomics defines two prognosis-related proteomic HCC subgroups. ARSs machinery is dysregulated in the aggressive subgroup, bearing potential as prognostic biomarkers. VARS1 promotes aggressiveness through the modulation of MAGI1, representing a novel targetable vulnerability in HCC.","PeriodicalId":19000,"journal":{"name":"Molecular Cancer","volume":"29 1","pages":""},"PeriodicalIF":37.3,"publicationDate":"2025-01-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142974782","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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