The harsh microenvironment in early breast cancer selects for a Warburg phenotype
Menée à l'aide d'échantillons tumoraux issus de patientes atteintes d'un carcinome canalaire in situ, d'un modèle murin et d'un modèle mathématique, cette étude identifie les conditions du microenvironnement tumoral qui favorisent le développement de cellules cancéreuses présentant un métabolisme qui privilégie la fermentation du glucose à son oxydation même en présence suffisante de dioxygène (métabolisme de type "Warburg")
Résumé en anglais
Glucose is converted to energy through “fermentation” or “oxidation.” Generally, if oxygen is available, cells will oxidize glucose to CO2 because it is more efficient than fermentation, which produces lactic acid. But Warburg noted that cancers ferment glucose at a “remarkable” rate even if O2 is available! This “Warburg Effect” is still misunderstood because it doesn’t make sense that a cell would ferment glucose when it could get much more energy by oxidizing it. The current paper goes to the heart of this problem by defining the microenvironmental conditions that exist in early cancers that would select for a Warburg Effect. This is important because such cells are much more aggressive and like to lead to cancers that are lethal.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.All study data are included in the article and supporting information.
