The harsh microenvironment in early breast cancer selects for a Warburg phenotype.
The harsh microenvironment in early breast cancer selects for a Warburg phenotype.
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DOI：
10.1073/pnas.2011342118
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发表时间：
2021-01-19
影响因子：
11.1
通讯作者：
Gillies RJ
中科院分区：
文献类型：
--
作者：
Damaghi M;West J;Robertson-Tessi M;Xu L;Ferrall-Fairbanks MC;Stewart PA;Persi E;Fridley BL;Altrock PM;Gatenby RA;Sims PA;Anderson ARA;Gillies RJ
葡萄糖通过“发酵”或“氧化”转化为能量。一般来说，如果有氧气，细胞会将葡萄糖氧化成二氧化碳，因为这比发酵产生乳酸更有效。但沃伯格指出，即使有氧气供应，癌症也会以“惊人的”速度发酵葡萄糖！这种“华宝效应”仍然被误解，因为当细胞可以通过氧化葡萄糖获得更多的能量时，它就不会发酵葡萄糖了。目前的论文通过定义早期癌症中存在的微环境条件来探讨这个问题的核心，这些微环境条件将选择沃堡效应。这一点很重要，因为这种细胞更具侵袭性，容易导致致命的癌症。导管原位癌(DCIS)恶劣的微环境对癌细胞施加了强大的进化选择压力。我们假设，导管中心附近的不良代谢条件导致了Warburg效应(WE)表型的出现，在这种表型中，即使在常氧条件下，细胞也能迅速将葡萄糖发酵成乳酸。为了验证这一假设，我们将低糖酵解的乳腺癌细胞置于不同的微环境选择压力下，使用缺氧、酸中毒、低糖和饥饿的组合长达数月，并分离单个克隆进行代谢和转录图谱分析。两个最苛刻的条件被选为构成表达的WE表型。对WE克隆的RNA测序分析表明，转录因子KLF4是WE表型的潜在诱导子。在染色的DCIS样本中，KLF4在微环境条件最恶劣的区域表达丰富。我们使用从体外结果校准的数学模型来模拟体内DCIS的表型进化。WE表型出现在坏死区附近代谢条件较差的地方。我们认为DCIS内恶劣的微环境通过结构性转录重编程选择WE表型，从而赋予生存优势并促进进一步的生长和侵袭。
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.
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影响因子：
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作者：
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通讯作者：
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