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

• Published in: Current biology Vol. 27; no. 3; pp. 392 - 400
• Main Authors: Lehmann, Steffi, te Boekhorst, Veronika, Odenthal, Julia, Bianchi, Roberta, van Helvert, Sjoerd, Ikenberg, Kristian, Ilina, Olga, Stoma, Szymon, Xandry, Jael, Jiang, Liying, Grenman, Reidar, Rudin, Markus, Friedl, Peter
• Format: Journal Article
• Language: English
• Published: England Elsevier Ltd 06-02-2017
• Subjects: amoeboid cell migration; Breast Neoplasms - metabolism; Breast Neoplasms - pathology; cancer invasion; Cell Adhesion; Cell Line, Tumor; Cell Movement; collective-to-amoeboid transition; Epithelial-Mesenchymal Transition; epithelial-to-mesenchymal transition; Female; Head and Neck Neoplasms - metabolism; Head and Neck Neoplasms - pathology; Humans; hypoxia; Hypoxia-Inducible Factor 1 - metabolism; hypoxia-inducible factors; Mechanotransduction, Cellular; Neoplasm Metastasis; Nuclear Proteins - metabolism; plasticity of cell migration; Tumor Hypoxia; Twist-Related Protein 1 - metabolism; hypoxia; plasticity of cell migration; cancer invasion; amoeboid cell migration; hypoxia-inducible factors; collective-to-amoeboid transition; epithelial-to-mesenchymal transition
• ISSN: 0960-9822; 1879-0445
• DOI: 10.1016/j.cub.2016.11.057

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.
[Display omitted]
•Hypoxia induces collective-to-amoeboid transition in epithelial cancer cells•Twist-dependent and -independent pathways mediate the switch to amoeboid movement•The hypoxia-induced amoeboid profile does not affect metastatic tumor cell seeding•EMT is compatible with mesenchymal and amoeboid movement
Lehmann et al. identify hypoxia, via HIF, as an inducer of collective-to-amoeboid transition in epithelial cancer cells in spheroid culture and in vivo. A fraction of the amoeboid cell subsets shows upregulation of nuclear Twist. Metabolic perturbation thus controls molecular plasticity toward EMT-dependent and -independent amoeboid cell movement.