title: Hypoxia Induces a HIF-1-Dependent Transition from Collective-to-Amoeboid Dissemination in Epithelial Cancer Cells.
abstract: Cancer metastases arise from a multi-step process that requires metastasizing tumor cells to adapt to signaling input from varying tissue environments [1]. As an early metastatic event, cancer cell dissemination occurs through different migration programs, including multicellular, collective, and single-cell mesenchymal or amoeboid migration [2-4]. Migration modes can interconvert based on changes in cell adhesion, cytoskeletal mechanotransduction [5], and/or proteolysis [6], most likely under the control of transcriptional programs such as the epithelial-to-mesenchymal transition (EMT) [7, 8]. However, how plasticity of tumor cell migration and EMT is spatiotemporally controlled and connected upon challenge by the tumor microenvironment remains unclear. Using 3D cultures of collectively invading breast and head and neck cancer spheroids, here we identify hypoxia, a hallmark of solid tumors [9], as an inducer of the collective-to-amoeboid transition (CAT), promoting the dissemination of amoeboid-moving single cells from collective invasion strands. Hypoxia-induced amoeboid detachment was driven by hypoxia-inducible factor 1 (HIF-1), followed the downregulation of E-cadherin, and produced heterogeneous cell subsets whose phenotype and migration were dependent (∼30%) or independent (∼70%) of Twist-mediated EMT. EMT-like and EMT-independent amoeboid cell subsets showed stable amoeboid movement over hours as well as leukocyte-like traits, including rounded morphology, matrix metalloproteinase (MMP)-independent migration, and nuclear deformation. Cancer cells undergoing pharmacological stabilization of HIFs retained their constitutive ability for early metastatic seeding in an experimental model of lung metastasis, indicating that hypoxia-induced CAT enhances cell release rather than early organ colonization. Induced by metabolic challenge, amoeboid movement may thus constitute a common endpoint of both EMT-dependent and EMT-independent cancer dissemination programs.
authors.affiliation: Department of Cell Biology, Radboud University Medical Center, 6525 GA Nijmegen, the Netherlands; Institute for Biomedical Engineering, ETH and University of Zurich, 8093 Zurich, Switzerland. Electronic address: lehmann@biomed.ee.ethz.ch.
authors.forename: Steffi
authors.initials: S
authors.lastname: Lehmann
authors.affiliation: Department of Cell Biology, Radboud University Medical Center, 6525 GA Nijmegen, the Netherlands; Department of Genitourinary Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
authors.forename: Veronika
authors.initials: V
authors.lastname: Te Boekhorst
authors.affiliation: Department of Cell Biology, Radboud University Medical Center, 6525 GA Nijmegen, the Netherlands; Department of Otolaryngology and Head and Neck Surgery, Radboud University Medical Center, 6525 EX Nijmegen, the Netherlands.
authors.forename: Julia
authors.initials: J
authors.lastname: Odenthal
authors.affiliation: Institute for Biomedical Engineering, ETH and University of Zurich, 8093 Zurich, Switzerland; Institute for Pharmaceutical Sciences, ETH Zurich, 8093 Zurich, Switzerland.
authors.forename: Roberta
authors.initials: R
authors.lastname: Bianchi
authors.affiliation: Department of Cell Biology, Radboud University Medical Center, 6525 GA Nijmegen, the Netherlands.
authors.forename: Sjoerd
authors.initials: S
authors.lastname: van Helvert
authors.affiliation: Institute for Pharmaceutical Sciences, ETH Zurich, 8093 Zurich, Switzerland; Institute of Pathology and Molecular Pathology, University Hospital Zurich, 8091 Zurich, Switzerland.
authors.forename: Kristian
authors.initials: K
authors.lastname: Ikenberg
authors.affiliation: Department of Cell Biology, Radboud University Medical Center, 6525 GA Nijmegen, the Netherlands.
authors.forename: Olga
authors.initials: O
authors.lastname: Ilina
authors.affiliation: Scientific Center for Optical and Electron Microscopy (ScopeM), ETH Zurich, 8093 Zurich, Switzerland.
authors.forename: Szymon
authors.initials: S
authors.lastname: Stoma
authors.affiliation: Institute for Biomedical Engineering, ETH and University of Zurich, 8093 Zurich, Switzerland.
authors.forename: Jael
authors.initials: J
authors.lastname: Xandry
authors.affiliation: Department of Genitourinary Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
authors.forename: Liying
authors.initials: L
authors.lastname: Jiang
authors.affiliation: Department of Otorhinolaryngology-Head and Neck Surgery, Turku University and Turku University Hospital, 20521 Turku, Finland.
authors.forename: Reidar
authors.initials: R
authors.lastname: Grenman
authors.affiliation: Institute for Biomedical Engineering, ETH and University of Zurich, 8093 Zurich, Switzerland; Institute of Pharmacology and Toxicology, University of Zurich, 8057 Zurich, Switzerland.
authors.forename: Markus
authors.initials: M
authors.lastname: Rudin
authors.affiliation: Department of Cell Biology, Radboud University Medical Center, 6525 GA Nijmegen, the Netherlands; Department of Genitourinary Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA; Cancer Genomics Center, 3584 CG Utrecht, the Netherlands. Electronic address: peter.friedl@radboudumc.nl.
authors.forename: Peter
authors.initials: P
authors.lastname: Friedl
mesh_terms: D001943:Breast Neoplasms / Q000378:metabolism / Q000473:pathology*; D002448:Cell Adhesion; D045744:Cell Line, Tumor; D002465:Cell Movement; D058750:Epithelial-Mesenchymal Transition; D005260:Female; D006258:Head and Neck Neoplasms / Q000378:metabolism / Q000473:pathology*; D006801:Humans; D051793:Hypoxia-Inducible Factor 1 / Q000378:metabolism*; D040542:Mechanotransduction, Cellular; D009362:Neoplasm Metastasis; D009687:Nuclear Proteins / Q000378:metabolism; D000072258:Tumor Hypoxia; D051879:Twist-Related Protein 1 / Q000378:metabolism
chemical_list: D051793:Hypoxia-Inducible Factor 1; D009687:Nuclear Proteins; C103173:TWIST1 protein, human; D051879:Twist-Related Protein 1
keywords: amoeboid cell migration; cancer invasion; collective-to-amoeboid transition; epithelial-to-mesenchymal transition; hypoxia; hypoxia-inducible factors; plasticity of cell migration