Nature Reviews Cancer最新文献

{"title":"New horizons in our understanding of precursor multiple myeloma and early interception","authors":"David M. Cordas dos Santos, Rosa Toenges, Luca Bertamini, Jean-Baptiste Alberge, Irene M. Ghobrial","doi":"10.1038/s41568-024-00755-x","DOIUrl":"10.1038/s41568-024-00755-x","url":null,"abstract":"Multiple myeloma is an incurable plasma cell malignancy that evolves over decades through the selection and malignant transformation of monoclonal plasma cells. The evolution from precursor states to symptomatic disease is characterized by an increasing complexity of genomic alterations within the plasma cells and a remodelling of the microenvironment towards an immunosuppressive state. Notably, in patients with advanced disease, similar mechanisms of tumour escape and immune dysfunction mediate resistance to modern T cell-based therapies, such as T cell-engaging bispecific antibodies and chimeric antigen receptor (CAR)-T cells. Thus, an increasing number of clinical trials are assessing the efficiency and safety of these therapies in individuals with newly diagnosed multiple myeloma and high-risk smoldering multiple myeloma. In this Review, we summarize the current knowledge about tumour intrinsic and extrinsic processes underlying progression from precursor states to symptomatic myeloma and discuss the rationale for early interception including the use of T cell-redirecting therapies. Multiple myeloma is a plasma cell malignancy that is currently incurable. Cordas dos Santos et al. describe how multiple myeloma arises from precursor states and how T cell-redirecting therapies might be used to intercept disease progression at these earlier stages to improve patient outcomes.","PeriodicalId":19055,"journal":{"name":"Nature Reviews Cancer","volume":"24 12","pages":"867-886"},"PeriodicalIF":72.5,"publicationDate":"2024-10-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142439736","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":"Epigenomic heterogeneity as a source of tumour evolution","authors":"Marthe Laisné, Mathieu Lupien, Céline Vallot","doi":"10.1038/s41568-024-00757-9","DOIUrl":"https://doi.org/10.1038/s41568-024-00757-9","url":null,"abstract":"<p>In the past decade, remarkable progress in cancer medicine has been achieved by the development of treatments that target DNA sequence variants. However, a purely genetic approach to treatment selection is hampered by the fact that diverse cell states can emerge from the same genotype. In multicellular organisms, cell-state heterogeneity is driven by epigenetic processes that regulate DNA-based functions such as transcription; disruption of these processes is a hallmark of cancer that enables the emergence of defective cell states. Advances in single-cell technologies have unlocked our ability to quantify the epigenomic heterogeneity of tumours and understand its mechanisms, thereby transforming our appreciation of how epigenomic changes drive cancer evolution. This Review explores the idea that epigenomic heterogeneity and plasticity act as a reservoir of cell states and therefore as a source of tumour evolution. Best practices to quantify epigenomic heterogeneity and explore its various causes and consequences are discussed, including epigenomic reprogramming, stochastic changes and lasting memory. The design of new therapeutic approaches to restrict epigenomic heterogeneity, with the long-term objective of limiting cancer development and progression, is also addressed.</p>","PeriodicalId":19055,"journal":{"name":"Nature Reviews Cancer","volume":"6 1","pages":""},"PeriodicalIF":78.5,"publicationDate":"2024-10-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142440383","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":"Immunoproteasome as a biomarker for immunotherapy","authors":"Radhakrishnan Sabarinathan","doi":"10.1038/s41568-024-00759-7","DOIUrl":"https://doi.org/10.1038/s41568-024-00759-7","url":null,"abstract":"In this Journal Club, Sabarinathan discusses a study suggesting immunoproteasome expression as a potential biomarker of response to immune checkpoint inhibition in melanoma.","PeriodicalId":19055,"journal":{"name":"Nature Reviews Cancer","volume":"9 1","pages":""},"PeriodicalIF":78.5,"publicationDate":"2024-10-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142439490","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":"Encoding spatial tumour dynamics with Starfysh","authors":"Siyu He","doi":"10.1038/s41568-024-00764-w","DOIUrl":"https://doi.org/10.1038/s41568-024-00764-w","url":null,"abstract":"In this Tools of the Trade article, Siyu He describes the development of Starfysh, a computational toolbox that integrates histology of complex tissues in spatial transcriptomic data analysis to characterize cell states.","PeriodicalId":19055,"journal":{"name":"Nature Reviews Cancer","volume":"2 1","pages":""},"PeriodicalIF":78.5,"publicationDate":"2024-10-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142404904","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":"Compressive stresses in cancer: characterization and implications for tumour progression and treatment","authors":"Julia A. Linke,&nbsp;Lance L. Munn,&nbsp;Rakesh K. Jain","doi":"10.1038/s41568-024-00745-z","DOIUrl":"10.1038/s41568-024-00745-z","url":null,"abstract":"Beyond their many well-established biological aberrations, solid tumours create an abnormal physical microenvironment that fuels cancer progression and confers treatment resistance. Mechanical forces impact tumours across a range of biological sizes and timescales, from rapid events at the molecular level involved in their sensing and transmission, to slower and larger-scale events, including clonal selection, epigenetic changes, cell invasion, metastasis and immune response. Owing to challenges with studying these dynamic stimuli in biological systems, the mechanistic understanding of the effects and pathways triggered by abnormally elevated mechanical forces remains elusive, despite clear correlations with cancer pathophysiology, aggressiveness and therapeutic resistance. In this Review, we examine the emerging and diverse roles of physical forces in solid tumours and provide a comprehensive framework for understanding solid stress mechanobiology. We first review the physiological importance of mechanical forces, especially compressive stresses, and discuss their defining characteristics, biological context and relative magnitudes. We then explain how abnormal compressive stresses emerge in tumours and describe the experimental challenges in investigating these mechanically induced processes. Finally, we discuss the clinical translation of mechanotherapeutics&nbsp;that alleviate solid stresses and their potential to synergize with chemotherapy, radiotherapy and immunotherapies. In this Review, Linke, Munn and Jain provide a framework for understanding solid stress mechanobiology, examine the emerging and diverse roles of elevated compressive stresses in solid tumours, and highlight the potential for targeting mechanical abnormalities in cancer.","PeriodicalId":19055,"journal":{"name":"Nature Reviews Cancer","volume":"24 11","pages":"768-791"},"PeriodicalIF":72.5,"publicationDate":"2024-10-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142397861","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":"Male melanoma comes of age","authors":"Daniela Senft","doi":"10.1038/s41568-024-00766-8","DOIUrl":"10.1038/s41568-024-00766-8","url":null,"abstract":"In a recent study published in Cell, Chhabra et al. identify age- and sex-dependent changes in skin fibroblasts that drive melanoma aggressiveness, with aged male fibroblasts promoting a slow-cycling, invasive state and resistance to targeted therapy in melanoma cells.","PeriodicalId":19055,"journal":{"name":"Nature Reviews Cancer","volume":"24 11","pages":"742-742"},"PeriodicalIF":72.5,"publicationDate":"2024-10-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142397858","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":"Cancer-induced systemic pre-conditioning of distant organs: building a niche for metastatic cells","authors":"Nicolas Rabas,&nbsp;Rute M. M. Ferreira,&nbsp;Stefania Di Blasio,&nbsp;Ilaria Malanchi","doi":"10.1038/s41568-024-00752-0","DOIUrl":"10.1038/s41568-024-00752-0","url":null,"abstract":"From their early genesis, tumour cells integrate with the surrounding normal cells to form an abnormal structure that is tightly integrated with the host organism via blood and lymphatic vessels and even neural associations. Using these connections, emerging cancers send a plethora of mediators that efficiently perturb the entire organism and induce changes in distant tissues. These perturbations serendipitously favour early metastatic establishment by promoting a more favourable tissue environment (niche) that supports the persistence of disseminated tumour cells within a foreign tissue. Because the establishment of early metastatic niches represents a key limiting step for metastasis, the creation of a more suitable pre-conditioned tissue strongly enhances metastatic success. In this Review, we provide an updated view of the mechanisms and mediators of primary tumours described so far that induce a pro-metastatic conditioning of distant organs, which favours early metastatic niche formation. We reflect on the nature of cancer-induced systemic conditioning, considering that non-cancer-dependent perturbations of tissue homeostasis are also able to trigger pro-metastatic conditioning. We argue that a more holistic view of the processes catalysing metastatic progression is needed to identify preventive or therapeutic opportunities. In this Review, Rabas et al. describe the mechanisms by which primary tumours precondition distal organs to favour metastatic colonization&nbsp;—&nbsp;a limiting step of metastasis&nbsp;—&nbsp;and discuss how non-cancer-dependent perturbations of tissue homeostasis are also able to trigger pro-metastatic conditioning, emphasizing the need for a holistic view to identify preventive or therapeutic opportunities.","PeriodicalId":19055,"journal":{"name":"Nature Reviews Cancer","volume":"24 12","pages":"829-849"},"PeriodicalIF":72.5,"publicationDate":"2024-10-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142397859","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":"Steering research on mRNA splicing in cancer towards clinical translation","authors":"Olga Anczukow,&nbsp;Frédéric H.-T. Allain,&nbsp;Brittany L. Angarola,&nbsp;Douglas L. Black,&nbsp;Angela N. Brooks,&nbsp;Chonghui Cheng,&nbsp;Ana Conesa,&nbsp;Edie I. Crosse,&nbsp;Eduardo Eyras,&nbsp;Ernesto Guccione,&nbsp;Sydney X. Lu,&nbsp;Karla M. Neugebauer,&nbsp;Priyanka Sehgal,&nbsp;Xiao Song,&nbsp;Zuzana Tothova,&nbsp;Juan Valcárcel,&nbsp;Kevin M. Weeks,&nbsp;Gene W. Yeo,&nbsp;Andrei Thomas-Tikhonenko","doi":"10.1038/s41568-024-00750-2","DOIUrl":"10.1038/s41568-024-00750-2","url":null,"abstract":"Splicing factors are affected by recurrent somatic mutations and copy number variations in several types of haematologic and solid malignancies, which is often seen as prima facie evidence that splicing aberrations can drive cancer initiation and progression. However, numerous spliceosome components also ‘moonlight’ in DNA repair and other cellular processes, making their precise role in cancer difficult to pinpoint. Still, few would deny that dysregulated mRNA splicing is a pervasive feature of most cancers. Correctly interpreting these molecular fingerprints can reveal novel tumour vulnerabilities and untapped therapeutic opportunities. Yet multiple technological challenges, lingering misconceptions, and outstanding questions hinder clinical translation. To start with, the general landscape of splicing aberrations in cancer is not well defined, due to limitations of short-read RNA sequencing not adept at resolving complete mRNA isoforms, as well as the shallow read depth inherent in long-read RNA-sequencing, especially at single-cell level. Although individual cancer-associated isoforms are known to contribute to cancer progression, widespread splicing alterations could be an equally important and, perhaps, more readily actionable feature of human cancers. This is to say that in addition to ‘repairing’ mis-spliced transcripts, possible therapeutic avenues include exacerbating splicing aberration with small-molecule spliceosome inhibitors, targeting recurrent splicing aberrations with&nbsp;synthetic lethal approaches, and training the immune system to recognize splicing-derived neoantigens. Although splicing factors are altered in cancer through mutations and copy number variations, their exact role remains challenging to define. In this Roadmap, Anczukow, Thomas-Tikhonenko and colleagues explore recent advances in splicing biology and provide guidance on leveraging these insights to facilitate the clinical application of compounds that target or exploit aberrant splicing patterns in cancer.","PeriodicalId":19055,"journal":{"name":"Nature Reviews Cancer","volume":"24 12","pages":"887-905"},"PeriodicalIF":72.5,"publicationDate":"2024-10-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142385076","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":"Four-pronged attack on PDAC","authors":"Gabrielle Brewer","doi":"10.1038/s41568-024-00765-9","DOIUrl":"10.1038/s41568-024-00765-9","url":null,"abstract":"Chibaya, DeMarco et al. investigated a combinatorial approach of delivering innate immune agonists and RAS pathway-targeted therapies to remodel the tumour microenvironment and improve PDAC drug response.","PeriodicalId":19055,"journal":{"name":"Nature Reviews Cancer","volume":"24 11","pages":"742-742"},"PeriodicalIF":72.5,"publicationDate":"2024-10-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142384150","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":"Challenging the status quo to improve the translational potential of preclinical oncology studies","authors":"Kate Connor, Anna Golebiewska, Annette T. Byrne","doi":"10.1038/s41568-024-00756-w","DOIUrl":"https://doi.org/10.1038/s41568-024-00756-w","url":null,"abstract":"The precision medicine era has precipitated inherent new challenges to the preclinical tumour biology field. Overall, continued poor clinical translatability of preclinical studies highlights the need to disrupt the status quo. Well-characterized models, ideally established in the orthotopic setting and, where feasible, treated with classical standard-of-care regimens, are mandated. In this Comment, Connor et al. discuss how the continued poor clinical translatability of preclinical studies highlights the need to mandate well-characterized models, ideally established in the orthotopic setting and, where feasible, treated with classical standard-of-care regimens.","PeriodicalId":19055,"journal":{"name":"Nature Reviews Cancer","volume":"6 1","pages":""},"PeriodicalIF":78.5,"publicationDate":"2024-10-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142383730","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}