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

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.

Agent-based computational modeling of glioblastoma predicts that stromal density is central to oncolytic virus efficacy

“…Our computational model was implemented leveraging the previously developed PhysiCell ( Ghaffarizadeh et al., 2018 ) (physics-based multicellular simulator), an agent-based simulator that models the interaction between cells and diffusing fields in dynamic tissue microenvironments. Below we provide a very brief overview of the PhysiCell software and direct the reader to physicell.org and the following publications for more information ( Ghaffarizadeh et al., 2018 ; Ozik et al., 2018 ; Rocha et al., 2021 ; Wang et al., 2021 ).…”

Detection of Hypoxia in Cancer Models: Significance, Challenges, and Advances

“…In this system, cells that experience hypoxia maintain permanent eGFP expression. Our studies showed a correlation of eGFP, Hypoxyprobe™, and HIF-1α expression in IF-labeled tissue sections of orthotopic tumors harvested from the mammary fat pad of mice [ 19 , 69 ]. Furthermore, the system allowed us to image and collect cells that experienced hypoxia in the primary tumor and metastasized to distant organs such as the lung and liver [ 19 , 70 ].…”

Hypoxia-Nitric Oxide Axis and the Associated Damage Molecular Pattern in Cutaneous Melanoma

“…Activation of hypoxia-inducible factors (HIFs) is an important response of cells at low oxygen concentrations. Three heterodimeric factors (HIF-1, HIF-2, and HIF-3) composed of oxygen-sensible alpha units and stable beta units, are described in the literature [ 4 , 5 ]. In physiological conditions, HIF-1a and HIF-2a are proteasomally degraded.…”

“…In hypoxic conditions, HIF-1a and HIF-2a are directed in the cellular nucleus and dimerize with HIF-1β. HIF-1 and HIF-2 are expressed in many tissues and regulate the expression of more than 1000 genes involved in hypoxia [ 4 , 5 , 6 , 7 , 8 , 9 , 10 , 11 ].…”