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 low-glycolytic 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 sequencing analysis of WE clones identified the transcription factor KLF4 as potential inducer of the WE phenotype. 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 WE phenotype through constitutive transcriptional reprogramming, thus conferring a survival advantage and facilitating further growth and invasion.
Profile Page: http://compmodelmatch.org/publications/13
PubMed ID: 33452133
Meetings: Finding Your Inner Modeler IV
Publication type: Journal
Journal: Proc Natl Acad Sci U S A
Citation: Proc Natl Acad Sci U S A. 2021 Jan 19;118(3). pii: 2011342118. doi: 10.1073/pnas.2011342118.
Date Published: 19th Jan 2021
Registered Mode: by PubMed ID
Created: 5th Aug 2021 at 17:45