Simona Migliozzi, Bruno Adabbo, Luciano Garofano, Fan Wu, Pedro Davila, Ricardo J. Komotar, Michael E. Ivan, Ashish H. Shah, Benjamin B. Currall, Sion Williams, Daniel Bilbao Cortes, Melinda Minucci Boone, Macarena I. de la Fuente, Sakir H. Gultekin, Michele Ceccarelli, Antonio Iavarone, Anna Lasorella
{"title":"Restraint of cancer cell plasticity by spatial homotypic clustering","authors":"Simona Migliozzi, Bruno Adabbo, Luciano Garofano, Fan Wu, Pedro Davila, Ricardo J. Komotar, Michael E. Ivan, Ashish H. Shah, Benjamin B. Currall, Sion Williams, Daniel Bilbao Cortes, Melinda Minucci Boone, Macarena I. de la Fuente, Sakir H. Gultekin, Michele Ceccarelli, Antonio Iavarone, Anna Lasorella","doi":"10.1016/j.ccell.2025.08.009","DOIUrl":null,"url":null,"abstract":"Tumor heterogeneity fueled by plasticity of cancer cells is a key to therapy failure. Here, we define the role of proximal communications of malignant cells in glioblastoma plasticity. We find that tumor cell state coherence is maximal in cells organized in homotypic clusters with defined relationships with non-malignant cells, whereas randomly dispersed cells downregulate the original state, acquire alternative phenotypes and exhibit changes in the microenvironment. We demonstrate the intrinsic propensity of glioblastoma cells to develop into clustered and dispersed spatial patterns in orthotopic mouse models and experimentally validate the cell state-specific mechanisms of cell-cell adhesion that prevent phenotype deviation with pharmacologic perturbations in patients-derived glioblastoma models. We establish the generality of “homotypic clustered cell identity” in circulating clustered and single breast cancer cells and show that the glioblastoma glycolytic-plurimetabolic dispersed cellular state uniquely confers shorter survival, thus assigning clinical significance to the spatial patterning of cancer cells in human tumors.","PeriodicalId":9670,"journal":{"name":"Cancer Cell","volume":"77 1","pages":""},"PeriodicalIF":44.5000,"publicationDate":"2025-09-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":null,"platform":"Semanticscholar","paperid":null,"PeriodicalName":"Cancer Cell","FirstCategoryId":"3","ListUrlMain":"https://doi.org/10.1016/j.ccell.2025.08.009","RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q1","JCRName":"CELL BIOLOGY","Score":null,"Total":0}
引用次数: 0
Abstract
Tumor heterogeneity fueled by plasticity of cancer cells is a key to therapy failure. Here, we define the role of proximal communications of malignant cells in glioblastoma plasticity. We find that tumor cell state coherence is maximal in cells organized in homotypic clusters with defined relationships with non-malignant cells, whereas randomly dispersed cells downregulate the original state, acquire alternative phenotypes and exhibit changes in the microenvironment. We demonstrate the intrinsic propensity of glioblastoma cells to develop into clustered and dispersed spatial patterns in orthotopic mouse models and experimentally validate the cell state-specific mechanisms of cell-cell adhesion that prevent phenotype deviation with pharmacologic perturbations in patients-derived glioblastoma models. We establish the generality of “homotypic clustered cell identity” in circulating clustered and single breast cancer cells and show that the glioblastoma glycolytic-plurimetabolic dispersed cellular state uniquely confers shorter survival, thus assigning clinical significance to the spatial patterning of cancer cells in human tumors.
期刊介绍:
Cancer Cell is a journal that focuses on promoting major advances in cancer research and oncology. The primary criteria for considering manuscripts are as follows:
Major advances: Manuscripts should provide significant advancements in answering important questions related to naturally occurring cancers.
Translational research: The journal welcomes translational research, which involves the application of basic scientific findings to human health and clinical practice.
Clinical investigations: Cancer Cell is interested in publishing clinical investigations that contribute to establishing new paradigms in the treatment, diagnosis, or prevention of cancers.
Insights into cancer biology: The journal values clinical investigations that provide important insights into cancer biology beyond what has been revealed by preclinical studies.
Mechanism-based proof-of-principle studies: Cancer Cell encourages the publication of mechanism-based proof-of-principle clinical studies, which demonstrate the feasibility of a specific therapeutic approach or diagnostic test.