Pub Date : 2023-05-04DOI: 10.1038/s41568-023-00567-5
Margarita Bartish, Madelyn J. Abraham, Christophe Gonçalves, Ola Larsson, Charlotte Rolny, Sonia V. del Rincón
Cells can rapidly adjust their proteomes in dynamic environments by regulating mRNA translation. There is mounting evidence that dysregulation of mRNA translation supports the survival and adaptation of cancer cells, which has stimulated clinical interest in targeting elements of the translation machinery and, in particular, components of the eukaryotic initiation factor 4F (eIF4F) complex such as eIF4E. However, the effect of targeting mRNA translation on infiltrating immune cells and stromal cells in the tumour microenvironment (TME) has, until recently, remained unexplored. In this Perspective article, we discuss how eIF4F-sensitive mRNA translation controls the phenotypes of key non-transformed cells in the TME, with an emphasis on the underlying therapeutic implications of targeting eIF4F in cancer. As eIF4F-targeting agents are in clinical trials, we propose that a broader understanding of their effect on gene expression in the TME will reveal unappreciated therapeutic vulnerabilities that could be used to improve the efficacy of existing cancer therapies. Eukaryotic initiation factor 4F (eIF4F) controls the translation of a subset of transcripts that include those encoding oncogenic proteins. In this Perspective article, Bartish et al. discuss the implications of targeting eIF4F on immune and stromal cells in the tumour microenvironment. In addition to discussing data from cancer models, the authors incorporate extensive data from non-cancer contexts to identify potential desirable or unwanted effects of eIF4F inhibition in these cells.
{"title":"The role of eIF4F-driven mRNA translation in regulating the tumour microenvironment","authors":"Margarita Bartish, Madelyn J. Abraham, Christophe Gonçalves, Ola Larsson, Charlotte Rolny, Sonia V. del Rincón","doi":"10.1038/s41568-023-00567-5","DOIUrl":"10.1038/s41568-023-00567-5","url":null,"abstract":"Cells can rapidly adjust their proteomes in dynamic environments by regulating mRNA translation. There is mounting evidence that dysregulation of mRNA translation supports the survival and adaptation of cancer cells, which has stimulated clinical interest in targeting elements of the translation machinery and, in particular, components of the eukaryotic initiation factor 4F (eIF4F) complex such as eIF4E. However, the effect of targeting mRNA translation on infiltrating immune cells and stromal cells in the tumour microenvironment (TME) has, until recently, remained unexplored. In this Perspective article, we discuss how eIF4F-sensitive mRNA translation controls the phenotypes of key non-transformed cells in the TME, with an emphasis on the underlying therapeutic implications of targeting eIF4F in cancer. As eIF4F-targeting agents are in clinical trials, we propose that a broader understanding of their effect on gene expression in the TME will reveal unappreciated therapeutic vulnerabilities that could be used to improve the efficacy of existing cancer therapies. Eukaryotic initiation factor 4F (eIF4F) controls the translation of a subset of transcripts that include those encoding oncogenic proteins. In this Perspective article, Bartish et al. discuss the implications of targeting eIF4F on immune and stromal cells in the tumour microenvironment. In addition to discussing data from cancer models, the authors incorporate extensive data from non-cancer contexts to identify potential desirable or unwanted effects of eIF4F inhibition in these cells.","PeriodicalId":19055,"journal":{"name":"Nature Reviews Cancer","volume":"23 6","pages":"408-425"},"PeriodicalIF":78.5,"publicationDate":"2023-05-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"9666606","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 : 2023-05-04DOI: 10.1038/s41568-023-00585-3
Gabrielle Brewer
In a recent Nature study, Hill et al. provide mechanistic evidence that air pollution promotes lung tumorigenesis in cells with pre-existing oncogenic mutations.
{"title":"Air pollution promotes tumorigenesis through pre-existing oncogenic mutations","authors":"Gabrielle Brewer","doi":"10.1038/s41568-023-00585-3","DOIUrl":"10.1038/s41568-023-00585-3","url":null,"abstract":"In a recent Nature study, Hill et al. provide mechanistic evidence that air pollution promotes lung tumorigenesis in cells with pre-existing oncogenic mutations.","PeriodicalId":19055,"journal":{"name":"Nature Reviews Cancer","volume":"23 6","pages":"350-350"},"PeriodicalIF":78.5,"publicationDate":"2023-05-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"9951727","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 : 2023-05-03DOI: 10.1038/s41568-023-00568-4
Jess D. Hebert, Joel W. Neal, Monte M. Winslow
Metastasis has long been understood to lead to the overwhelming majority of cancer-related deaths. However, our understanding of the metastatic process, and thus our ability to prevent or eliminate metastases, remains frustratingly limited. This is largely due to the complexity of metastasis, which is a multistep process that likely differs across cancer types and is greatly influenced by many aspects of the in vivo microenvironment. In this Review, we discuss the key variables to consider when designing assays to study metastasis: which source of metastatic cancer cells to use and where to introduce them into mice to address different questions of metastasis biology. We also examine methods that are being used to interrogate specific steps of the metastatic cascade in mouse models, as well as emerging techniques that may shed new light on previously inscrutable aspects of metastasis. Finally, we explore approaches for developing and using anti-metastatic therapies, and how mouse models can be used to test them. Although metastasis is the leading cause of cancer-related deaths, our understanding of the process is limited. In this Review, Hebert et al. discuss the key features of various models of metastasis, highlighting their advantages and disadvantages for further dissecting mechanisms of metastasis and developing metastasis-targeted therapies.
{"title":"Dissecting metastasis using preclinical models and methods","authors":"Jess D. Hebert, Joel W. Neal, Monte M. Winslow","doi":"10.1038/s41568-023-00568-4","DOIUrl":"10.1038/s41568-023-00568-4","url":null,"abstract":"Metastasis has long been understood to lead to the overwhelming majority of cancer-related deaths. However, our understanding of the metastatic process, and thus our ability to prevent or eliminate metastases, remains frustratingly limited. This is largely due to the complexity of metastasis, which is a multistep process that likely differs across cancer types and is greatly influenced by many aspects of the in vivo microenvironment. In this Review, we discuss the key variables to consider when designing assays to study metastasis: which source of metastatic cancer cells to use and where to introduce them into mice to address different questions of metastasis biology. We also examine methods that are being used to interrogate specific steps of the metastatic cascade in mouse models, as well as emerging techniques that may shed new light on previously inscrutable aspects of metastasis. Finally, we explore approaches for developing and using anti-metastatic therapies, and how mouse models can be used to test them. Although metastasis is the leading cause of cancer-related deaths, our understanding of the process is limited. In this Review, Hebert et al. discuss the key features of various models of metastasis, highlighting their advantages and disadvantages for further dissecting mechanisms of metastasis and developing metastasis-targeted therapies.","PeriodicalId":19055,"journal":{"name":"Nature Reviews Cancer","volume":"23 6","pages":"391-407"},"PeriodicalIF":78.5,"publicationDate":"2023-05-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"9720517","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}
{"title":"Untangling the mechanisms of cancer predisposition","authors":"Giovana Tardin Torrezan","doi":"10.1038/s41568-023-00577-3","DOIUrl":"10.1038/s41568-023-00577-3","url":null,"abstract":"In this Journal Club, Giovana Tardin Torrezan discusses a study that analyses the role of germline pathogenic variants in tumorigenesis.","PeriodicalId":19055,"journal":{"name":"Nature Reviews Cancer","volume":"23 7","pages":"429-429"},"PeriodicalIF":78.5,"publicationDate":"2023-05-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"9694432","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 : 2023-04-28DOI: 10.1038/s41568-023-00582-6
Zhenqin Wu
In this Tools of the Trade article, Zhenqin Wu describes the development and use of SPACE-GM, a graph deep learning tool that enables the detection of spatial cellular structures predictive of outcomes of patients with cancer.
在这篇 "贸易工具"（Tools of the Trade）文章中，吴振钦介绍了 SPACE-GM 的开发和使用情况，SPACE-GM 是一种图形深度学习工具，能够检测预测癌症患者预后的空间细胞结构。
{"title":"Identifying spatial cellular structures with SPACE-GM","authors":"Zhenqin Wu","doi":"10.1038/s41568-023-00582-6","DOIUrl":"10.1038/s41568-023-00582-6","url":null,"abstract":"In this Tools of the Trade article, Zhenqin Wu describes the development and use of SPACE-GM, a graph deep learning tool that enables the detection of spatial cellular structures predictive of outcomes of patients with cancer.","PeriodicalId":19055,"journal":{"name":"Nature Reviews Cancer","volume":"23 8","pages":"508-508"},"PeriodicalIF":78.5,"publicationDate":"2023-04-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"10231339","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 : 2023-04-27DOI: 10.1038/s41568-023-00581-7
Anna Dart
Blanpain and colleagues provide evidence that the small RHO GTPase, RHOJ, mediates resistance to chemotherapy in tumour cells that have undergone epithelial-to-mesenchymal transition by enabling these cells to tolerate replicative stress and promote DNA damage repair.
Blanpain 及其同事提供的证据表明，小 RHO GTPase RHOJ 能够使经历了上皮到间质转化的肿瘤细胞耐受复制压力并促进 DNA 损伤修复，从而介导这些细胞对化疗的耐受性。
{"title":"EMT in chemoresistance","authors":"Anna Dart","doi":"10.1038/s41568-023-00581-7","DOIUrl":"10.1038/s41568-023-00581-7","url":null,"abstract":"Blanpain and colleagues provide evidence that the small RHO GTPase, RHOJ, mediates resistance to chemotherapy in tumour cells that have undergone epithelial-to-mesenchymal transition by enabling these cells to tolerate replicative stress and promote DNA damage repair.","PeriodicalId":19055,"journal":{"name":"Nature Reviews Cancer","volume":"23 6","pages":"349-349"},"PeriodicalIF":78.5,"publicationDate":"2023-04-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"9953727","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 : 2023-04-24DOI: 10.1038/s41568-023-00565-7
Patricia P. Centeno, Valeria Pavet, Richard Marais
Over the past decade, melanoma has led the field in new cancer treatments, with impressive gains in on-treatment survival but more modest improvements in overall survival. Melanoma presents heterogeneity and transcriptional plasticity that recapitulates distinct melanocyte developmental states and phenotypes, allowing it to adapt to and eventually escape even the most advanced treatments. Despite remarkable advances in our understanding of melanoma biology and genetics, the melanoma cell of origin is still fiercely debated because both melanocyte stem cells and mature melanocytes can be transformed. Animal models and high-throughput single-cell sequencing approaches have opened new opportunities to address this question. Here, we discuss the melanocytic journey from the neural crest, where they emerge as melanoblasts, to the fully mature pigmented melanocytes resident in several tissues. We describe a new understanding of melanocyte biology and the different melanocyte subpopulations and microenvironments they inhabit, and how this provides unique insights into melanoma initiation and progression. We highlight recent findings on melanoma heterogeneity and transcriptional plasticity and their implications for exciting new research areas and treatment opportunities. The lessons from melanocyte biology reveal how cells that are present to protect us from the damaging effects of ultraviolet radiation reach back to their origins to become a potentially deadly cancer. This Review outlines how the developmental pathways that are involved in melanocyte development and skin pigmentation are highjacked by melanoma cells to drive melanomagenesis, progression and therapy resistance.
{"title":"The journey from melanocytes to melanoma","authors":"Patricia P. Centeno, Valeria Pavet, Richard Marais","doi":"10.1038/s41568-023-00565-7","DOIUrl":"10.1038/s41568-023-00565-7","url":null,"abstract":"Over the past decade, melanoma has led the field in new cancer treatments, with impressive gains in on-treatment survival but more modest improvements in overall survival. Melanoma presents heterogeneity and transcriptional plasticity that recapitulates distinct melanocyte developmental states and phenotypes, allowing it to adapt to and eventually escape even the most advanced treatments. Despite remarkable advances in our understanding of melanoma biology and genetics, the melanoma cell of origin is still fiercely debated because both melanocyte stem cells and mature melanocytes can be transformed. Animal models and high-throughput single-cell sequencing approaches have opened new opportunities to address this question. Here, we discuss the melanocytic journey from the neural crest, where they emerge as melanoblasts, to the fully mature pigmented melanocytes resident in several tissues. We describe a new understanding of melanocyte biology and the different melanocyte subpopulations and microenvironments they inhabit, and how this provides unique insights into melanoma initiation and progression. We highlight recent findings on melanoma heterogeneity and transcriptional plasticity and their implications for exciting new research areas and treatment opportunities. The lessons from melanocyte biology reveal how cells that are present to protect us from the damaging effects of ultraviolet radiation reach back to their origins to become a potentially deadly cancer. This Review outlines how the developmental pathways that are involved in melanocyte development and skin pigmentation are highjacked by melanoma cells to drive melanomagenesis, progression and therapy resistance.","PeriodicalId":19055,"journal":{"name":"Nature Reviews Cancer","volume":"23 6","pages":"372-390"},"PeriodicalIF":78.5,"publicationDate":"2023-04-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"9658154","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 : 2023-04-20DOI: 10.1038/s41568-023-00562-w
Benjamin Ruf, Tim F. Greten, Firouzeh Korangy
Immunotherapies targeting conventional T cells have revolutionized systemic treatment for many cancers, yet only a subset of patients benefit from these approaches. A better understanding of the complex immune microenvironment of tumours is needed to design the next generation of immunotherapeutics. Innate lymphoid cells (ILCs) and innate-like T cells (ILTCs) are abundant, tissue-resident lymphocytes that have recently been shown to have critical roles in many types of cancers. ILCs and ILTCs rapidly respond to changes in their surrounding environment and act as the first responders to bridge innate and adaptive immunity. This places ILCs and ILTCs as pivotal orchestrators of the final antitumour immune response. In this Review, we outline hallmarks of ILCs and ILTCs and discuss their emerging role in antitumour immunity, as well as the pathophysiological adaptations leading to their pro-tumorigenic function. We explore the pleiotropic, in parts redundant and sometimes opposing, mechanisms that underlie the delicate interplay between the different subsets of ILCs and ILTCs. Finally, we highlight their role in amplifying and complementing conventional T cell functions and summarize immunotherapeutic strategies for targeting ILCs and ILTCs in cancer. Ruf et al. discuss the emerging roles of innate lymphoid cells and innate-like T cells in cancer immunity. The authors highlight their role in bridging adaptive and innate immunity, as well as their potential as immunotherapeutic targets.
{"title":"Innate lymphoid cells and innate-like T cells in cancer — at the crossroads of innate and adaptive immunity","authors":"Benjamin Ruf, Tim F. Greten, Firouzeh Korangy","doi":"10.1038/s41568-023-00562-w","DOIUrl":"10.1038/s41568-023-00562-w","url":null,"abstract":"Immunotherapies targeting conventional T cells have revolutionized systemic treatment for many cancers, yet only a subset of patients benefit from these approaches. A better understanding of the complex immune microenvironment of tumours is needed to design the next generation of immunotherapeutics. Innate lymphoid cells (ILCs) and innate-like T cells (ILTCs) are abundant, tissue-resident lymphocytes that have recently been shown to have critical roles in many types of cancers. ILCs and ILTCs rapidly respond to changes in their surrounding environment and act as the first responders to bridge innate and adaptive immunity. This places ILCs and ILTCs as pivotal orchestrators of the final antitumour immune response. In this Review, we outline hallmarks of ILCs and ILTCs and discuss their emerging role in antitumour immunity, as well as the pathophysiological adaptations leading to their pro-tumorigenic function. We explore the pleiotropic, in parts redundant and sometimes opposing, mechanisms that underlie the delicate interplay between the different subsets of ILCs and ILTCs. Finally, we highlight their role in amplifying and complementing conventional T cell functions and summarize immunotherapeutic strategies for targeting ILCs and ILTCs in cancer. Ruf et al. discuss the emerging roles of innate lymphoid cells and innate-like T cells in cancer immunity. The authors highlight their role in bridging adaptive and innate immunity, as well as their potential as immunotherapeutic targets.","PeriodicalId":19055,"journal":{"name":"Nature Reviews Cancer","volume":"23 6","pages":"351-371"},"PeriodicalIF":78.5,"publicationDate":"2023-04-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"9720490","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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