The harsh microenvironment in early breast cancer selects for a Warburg phenotype

Damaghi, Mehdi; West, Jeffrey; Robertson-Tessi, Mark; Xu, Liping; Ferrall‐Fairbanks, Meghan C.; Stewart, Paul A.; Persi, Erez; Fridley, Brooke L.; Altrock, Philipp M.; Gatenby, Robert A.; Sims, Peter A.; Anderson, Alexander R.A.; Gillies, Robert J.

doi:10.1073/pnas.2011342118

Cited by 109 publications

(100 citation statements)

References 55 publications

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“…We propose an alternative to this canonical view, building on principles of evolutionary dynamics (Gatenby and Gillies, 2004b). Aerobic glycolysis is such a commonly observed phenotype of aggressive cancers (Rizwan et al, 2013; Yu et al, 2015), we argue that it MUST confer some selective advantage for tumor growth (Damaghi et al, 2021). An inherent consequence of glycolysis is lactic acid production, and we propose that acid secretion per se renders cells more competitive, despite the energetic cost (Gatenby et al, 2006b; Gillies et al, 2008).…”

Section: Introductionmentioning

confidence: 85%

Proton export drives the Warburg Effect

Russell

Kam

et al. 2021

Preprint

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Aggressive cancers commonly ferment glucose to lactic acid at high rates, even in the presence of oxygen. This is known as aerobic glycolysis, or the “Warburg Effect”. It is widely assumed that this is a consequence of the upregulation of glycolytic enzymes. Oncogenic drivers can increase the expression of most proteins in the glycolytic pathway, including the terminal step of exporting H+ equivalents from the cytoplasm. Proton exporters maintain an alkaline cytoplasmic pH, which can enhance all glycolytic enzyme activities, even in the absence of oncogene-related expression changes. Based on this observation, we hypothesized that increased uptake and fermentative metabolism of glucose could be driven by the expulsion of H+ equivalents from the cell. To test this hypothesis, we stably transfected lowly-glycolytic MCF-7, U2-OS, and glycolytic HEK293 cells to express proton exporting systems: either PMA1 (yeast H+-ATPase) or CAIX (carbonic anhydrase 9). The expression of either exporter in vitro enhanced aerobic glycolysis as measured by glucose consumption, lactate production, and extracellular acidification rate. This resulted in an increased intracellular pH, and metabolomic analyses indicated that this was associated with an increased flux of all glycolytic enzymes upstream of pyruvate kinase. These cells also demonstrated increased migratory and invasive phenotypes in vitro, and these were recapitulated in vivo by more aggressive behavior, whereby the acid-producing cells formed higher grade tumors with higher rates of metastases. Neutralizing tumor acidity with oral buffers reduced the metastatic burden. Therefore, cancer cells with increased H+ export increase intracellular alkalization, even without oncogenic driver mutations, and this is sufficient to alter cancer metabolism towards a Warburg phenotype.

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Section: Introductionmentioning

confidence: 85%

Proton export drives the Warburg Effect

Russell

Kam

et al. 2021

Preprint

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“…Although AFR and EOR scores have various values in different CGEMs, we noticed that higher AFR values denote more Warburg phenotype cancer cells [20]. Interestingly, it has been recently proposed that ATP plays a major role in the fitness of Warburg cells in their variable microenvironment [48]. Then, we used a gene set hallmark of cancer to quantify and validate the cancerous molecular signature of CGEMs.…”

Section: Assessment Of Metabolic Hallmarks Of Cancer In All Cgemsmentioning

confidence: 90%

Exploring the Metabolic Heterogeneity of Cancers: A Benchmark Study of Context-Specific Models

Jalili

Scharm²,

Damaghi³

et al. 2021

JPM

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Metabolic heterogeneity is a hallmark of cancer and can distinguish a normal phenotype from a cancer phenotype. In the systems biology domain, context-specific models facilitate extracting physiologically relevant information from high-quality data. Here, to utilize the heterogeneity of metabolic patterns to discover biomarkers of all cancers, we benchmarked thousands of context-specific models using well-established algorithms for the integration of omics data into the generic human metabolic model Recon3D. By analyzing the active reactions capable of carrying flux and their magnitude through flux balance analysis, we proved that the metabolic pattern of each cancer is unique and could act as a cancer metabolic fingerprint. Subsequently, we searched for proper feature selection methods to cluster the flux states characterizing each cancer. We employed PCA-based dimensionality reduction and a random forest learning algorithm to reveal reactions containing the most relevant information in order to effectively identify the most influential fluxes. Conclusively, we discovered different pathways that are probably the main sources for metabolic heterogeneity in cancers. We designed the GEMbench website to interactively present the data, methods, and analysis results.

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“…By contrast, the Warburg effect is commonly observed in ductal carcinomas in situ (DCIS). In early intraductal breast cancers, the Warburg effect emerges in the poor metabolic conditions [65]. Cancer cells adapt to harsh microenvironments with more aggressive and dedifferentiated phenotypes.…”

Section: The Metabolic Reprogramming and Molecular Diversity Of Primary Breast Cancersmentioning

confidence: 99%

Metabolic Stress Adaptations Underlie Mammary Gland Morphogenesis and Breast Cancer Progression

Wang

2021

Cells

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Breast cancers display dynamic reprogrammed metabolic activities as cancers develop from premalignant lesions to primary tumors, and then metastasize. Numerous advances focus on how tumors develop pro-proliferative metabolic signaling that differs them from adjacent, non-transformed epithelial tissues. This leads to targetable oncogene-driven liabilities among breast cancer subtypes. Other advances demonstrate how microenvironments trigger stress-response at single-cell resolution. Microenvironmental heterogeneities give rise to cell regulatory states in cancer cell spheroids in three-dimensional cultures and at stratified terminal end buds during mammary gland morphogenesis, where stress and survival signaling juxtapose. The cell-state specificity in stress signaling networks recapture metabolic evolution during cancer progression. Understanding lineage-specific metabolic phenotypes in experimental models is useful for gaining a deeper understanding of subtype-selective breast cancer metabolism.

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The harsh microenvironment in early breast cancer selects for a Warburg phenotype

Cited by 109 publications

References 55 publications

Proton export drives the Warburg Effect

Proton export drives the Warburg Effect

Exploring the Metabolic Heterogeneity of Cancers: A Benchmark Study of Context-Specific Models

Metabolic Stress Adaptations Underlie Mammary Gland Morphogenesis and Breast Cancer Progression

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