RT Journal Article
SR Electronic
T1 The Harsh Microenvironment in Early Breast Cancer Select for a Warburg Phenotype
JF bioRxiv
FD Cold Spring Harbor Laboratory
SP 2020.04.07.029975
DO 10.1101/2020.04.07.029975
A1 Mehdi Damaghi
A1 Jeffrey West
A1 Mark Robertson-Tessi
A1 Liping Xu
A1 Meghan C. Ferrall-Fairbanks
A1 Paul A. Stewart
A1 Erez Persi
A1 Brooke L. Fridley
A1 Philipp M. Altrock
A1 Robert A. Gatenby
A1 Peter A. Sims
A1 Alexander R. A. Anderson
A1 Robert J. Gillies
YR 2020
UL http://biorxiv.org/content/early/2020/04/08/2020.04.07.029975.abstract
AB The harsh microenvironment of ductal carcinoma in situ (DCIS) exerts strong evolutionary selection pressures on cancer cells. We hypothesize that the poor metabolic conditions near the ductal center foment the emergence of a Warburg Effect (WE) phenotype, wherein cells rapidly ferment glucose to lactic acid, even in normoxia. To test this hypothesis, we subjected pre-malignant breast cancer cells to different microenvironmental selection pressures using combinations of hypoxia, acidosis, low glucose, and starvation for many months, and isolated single clones for metabolic and transcriptomic profiling. The two harshest conditions selected for constitutively expressed WE phenotypes. RNA-seq analysis of WE clones identified the transcription factors NFкB and KLF4 as potential inducers of the WE phenotype. NFкB was highly phosphorylated in the glycolytic clones. In stained DCIS samples, KLF4 expression was enriched in the area with the harshest microenvironmental conditions. We simulated in vivo DCIS phenotypic evolution using a mathematical model calibrated from the in vitro results. The WE phenotype emerged in the poor metabolic conditions near the necrotic core. We propose that harsh microenvironments within DCIS select for a Warburg phenotype through constitutive transcriptional reprogramming, thus conferring a survival advantage and facilitating further growth and invasion.