A persistent invasive phenotype in post-hypoxic tumor cells is revealed by fate mapping and computational modeling
Heber L. Rocha,
Inês Godet,
Furkan Kurtoglu,
John Metzcar,
Kali Konstantinopoulos,
Soumitra Bhoyar,
Daniele M. Gilkes,
Paul Macklin
Affiliations
Heber L. Rocha
Department of Intelligent Systems Engineering, Indiana University, Bloomington, IN 47408, USA
Inês Godet
Department of Oncology, The Sidney Kimmel Comprehensive Cancer Center, The Johns Hopkins University School of Medicine, Baltimore, MD 21231, USA; Department of Chemical and Biomolecular Engineering, The Johns Hopkins University, Baltimore, MD 21218, USA
Furkan Kurtoglu
Department of Intelligent Systems Engineering, Indiana University, Bloomington, IN 47408, USA
John Metzcar
Department of Intelligent Systems Engineering, Indiana University, Bloomington, IN 47408, USA; Department of Informatics, Indiana University, Bloomington, IN 47408, USA
Kali Konstantinopoulos
Department of Intelligent Systems Engineering, Indiana University, Bloomington, IN 47408, USA
Soumitra Bhoyar
Department of Oncology, The Sidney Kimmel Comprehensive Cancer Center, The Johns Hopkins University School of Medicine, Baltimore, MD 21231, USA; Department of Chemical and Biomolecular Engineering, The Johns Hopkins University, Baltimore, MD 21218, USA
Daniele M. Gilkes
Department of Oncology, The Sidney Kimmel Comprehensive Cancer Center, The Johns Hopkins University School of Medicine, Baltimore, MD 21231, USA; Department of Chemical and Biomolecular Engineering, The Johns Hopkins University, Baltimore, MD 21218, USA; Cellular and Molecular Medicine Program, The Johns Hopkins University School of Medicine, Baltimore, MD 21231, USA
Paul Macklin
Department of Intelligent Systems Engineering, Indiana University, Bloomington, IN 47408, USA; Corresponding author
Summary: Hypoxia is a critical factor in solid tumors that has been associated with cancer progression and aggressiveness. We recently developed a hypoxia fate mapping system to trace post-hypoxic cells within a tumor for the first time. This approach uses an oxygen-dependent fluorescent switch and allowed us to measure key biological features such as oxygen distribution, cell proliferation, and migration. We developed a computational model to investigate the motility and phenotypic persistence of hypoxic and post-hypoxic cells during tumor progression. The cellular behavior was defined by phenotypic persistence time, cell movement bias, and the fraction of cells that respond to an enhanced migratory stimulus. This work combined advanced cell tracking and imaging techniques with mathematical modeling, to reveal that a persistent invasive migratory phenotype that develops under hypoxia is required for cellular escape into the surrounding tissue, promoting the formation of invasive structures (“plumes”) that expand toward the oxygenated tumor regions.
