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

doi:10.1016/j.isci.2021.102935

A persistent invasive phenotype in post-hypoxic tumor cells is revealed by fate mapping and computational modeling

iScience. 2021 Aug 4;24(9):102935. doi: 10.1016/j.isci.2021.102935. eCollection 2021 Sep 24.

Authors

Heber L Rocha¹, Inês Godet^{2

3}, Furkan Kurtoglu¹, John Metzcar^{1

4}, Kali Konstantinopoulos¹, Soumitra Bhoyar^{2

3}, Daniele M Gilkes^{2

3

5}, Paul Macklin¹

Affiliations

¹ Department of Intelligent Systems Engineering, Indiana University, Bloomington, IN 47408, USA.
² Department of Oncology, The Sidney Kimmel Comprehensive Cancer Center, The Johns Hopkins University School of Medicine, Baltimore, MD 21231, USA.
³ Department of Chemical and Biomolecular Engineering, The Johns Hopkins University, Baltimore, MD 21218, USA.
⁴ Department of Informatics, Indiana University, Bloomington, IN 47408, USA.
⁵ Cellular and Molecular Medicine Program, The Johns Hopkins University School of Medicine, Baltimore, MD 21231, USA.

Abstract

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.

Keywords: Cancer; Cancer systems biology; Cell biology; Systems biology.