@article{b87baa3dc9794b12b3ff57ae57495a92,
title = "Fate-mapping post-hypoxic tumor cells reveals a ROS-resistant phenotype that promotes metastasis",
abstract = "Hypoxia is known to be detrimental in cancer and contributes to its development. In this work, we present an approach to fate-map hypoxic cells in vivo in order to determine their cellular response to physiological O2 gradients as well as to quantify their contribution to metastatic spread. We demonstrate the ability of the system to fate-map hypoxic cells in 2D, and in 3D spheroids and organoids. We identify distinct gene expression patterns in cells that experienced intratumoral hypoxia in vivo compared to cells exposed to hypoxia in vitro. The intratumoral hypoxia gene-signature is a better prognostic indicator for distant metastasis-free survival. Post-hypoxic tumor cells have an ROS-resistant phenotype that provides a survival advantage in the bloodstream and promotes their ability to establish overt metastasis. Post-hypoxic cells retain an increase in the expression of a subset of hypoxia-inducible genes at the metastatic site, suggesting the possibility of a {\textquoteleft}hypoxic memory.{\textquoteright}",
author = "In{\^e}s Godet and Shin, {Yu Jung} and Ju, {Julia A.} and Ye, {I. Chae} and Guannan Wang and Gilkes, {Daniele M.}",
note = "Funding Information: We thank Dr. Denis Wirtz, Dr. Pei-Hsun Wu, Dr. Andrew Ewald, Dr. Ben Ho Park, Dr. Saraswati Sukumar, Dr. Dipali Sharma, Soumitra Bhoyar, and Josh DiGiacomo for their feedback over the course of this study. We particularly thank Dr. Sukumar for guidance with the intraductal mouse model. Dr. Hanhvy Bui (IIC Flow Cytometry Core) and Dr. Jessica Gucwa (SKCCC Flow Cytometry Core) assisted with flow cytometry. Marc Rosen, Jisu Shin, and Shyanne Salen assisted with tail-vein injections, migration tracking and analysis, and organoid generation, respectively. Work in the Gilkes lab is supported by U54-CA210173 (NCI), R00-CA181352 (NCI), The V Scholar Foundation, Susan G. Komen Foundation (CCR17483484), The Jayne Koskinas Ted Giovanis Foundation for Health and Policy, Cindy Rosencrans Fund for Metastatic Triple-Negative Breast Cancer, The Emerson Collective, and the SKCCC Core Grant (P50CA006973 (NCI)). Cartoons included in the display items of this work were adapted from Servier Medical Art licensed under a Creative Commons Attribution 3.0 Unported License (smart.servier.com). Publisher Copyright: {\textcopyright} 2019, The Author(s).",
year = "2019",
month = dec,
day = "1",
doi = "10.1038/s41467-019-12412-1",
language = "English (US)",
volume = "10",
journal = "Nature communications",
issn = "2041-1723",
publisher = "Nature Publishing Group",
number = "1",
}