TY - JOUR
T1 - Hypoxia Induces a HIF-1-Dependent Transition from Collective-to-Amoeboid Dissemination in Epithelial Cancer Cells
AU - Lehmann, Steffi
AU - te Boekhorst, Veronika
AU - Odenthal, Julia
AU - Bianchi, Roberta
AU - van Helvert, Sjoerd
AU - Ikenberg, Kristian
AU - Ilina, Olga
AU - Stoma, Szymon
AU - Xandry, Jael
AU - Jiang, Liying
AU - Grenman, Reidar
AU - Rudin, Markus
AU - Friedl, Peter
N1 - Funding Information:
We gratefully acknowledge Christiane Mittmann for expert technical assistance and Michael Detmar for providing essential laboratory infrastructure and helpful discussions. This work was supported by the European Molecular Biology Organization (EMBO ALTF 365-2010; long-term fellowship to S.L.), the Netherlands’ Science Organization (NWO; VICI-918.11.626) and Cancer Genomics Center (application number 024.001.028), the Netherlands and the European Research Council (617430-DEEPINSIGHT to P.F.), the Swiss National Science Foundation (grant CRSII3_136217 to M.R.), the KFSP Tumor Oxygenation of the University of Zurich (to M.R.), the Sassella Foundation and Promedica Foundation (to K.I.), and a Rosalie B. Hite Fellowship from the UT Graduate School for Biomedical Sciences (to V.t.B.).
Publisher Copyright:
© 2017
PY - 2017/2/6
Y1 - 2017/2/6
N2 - 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.
AB - 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.
KW - amoeboid cell migration
KW - cancer invasion
KW - collective-to-amoeboid transition
KW - epithelial-to-mesenchymal transition
KW - hypoxia
KW - hypoxia-inducible factors
KW - plasticity of cell migration
UR - http://www.scopus.com/inward/record.url?scp=85009473728&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85009473728&partnerID=8YFLogxK
U2 - 10.1016/j.cub.2016.11.057
DO - 10.1016/j.cub.2016.11.057
M3 - Article
C2 - 28089517
AN - SCOPUS:85009473728
SN - 0960-9822
VL - 27
SP - 392
EP - 400
JO - Current Biology
JF - Current Biology
IS - 3
ER -