Hypoxia Induces a HIF-1-Dependent Transition from Collective-to-Amoeboid Dissemination in Epithelial Cancer Cells

Steffi Lehmann, Veronika te Boekhorst, Julia Odenthal, Roberta Bianchi, Sjoerd van Helvert, Kristian Ikenberg, Olga Ilina, Szymon Stoma, Jael Xandry, Liying Jiang, Reidar Grenman, Markus Rudin, Peter Friedl

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32 Scopus citations


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.

Original languageEnglish (US)
Pages (from-to)392-400
Number of pages9
JournalCurrent Biology
Issue number3
StatePublished - Feb 6 2017



  • amoeboid cell migration
  • cancer invasion
  • collective-to-amoeboid transition
  • epithelial-to-mesenchymal transition
  • hypoxia
  • hypoxia-inducible factors
  • plasticity of cell migration

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)
  • Agricultural and Biological Sciences(all)

Cite this

Lehmann, S., te Boekhorst, V., Odenthal, J., Bianchi, R., van Helvert, S., Ikenberg, K., Ilina, O., Stoma, S., Xandry, J., Jiang, L., Grenman, R., Rudin, M., & Friedl, P. (2017). Hypoxia Induces a HIF-1-Dependent Transition from Collective-to-Amoeboid Dissemination in Epithelial Cancer Cells. Current Biology, 27(3), 392-400. https://doi.org/10.1016/j.cub.2016.11.057