LKB1 Inactivation Elicits a Redox Imbalance to Modulate Non-small Cell Lung Cancer Plasticity and Therapeutic Response.
LKB1 Inactivation Elicits a Redox Imbalance to Modulate Non-small Cell Lung Cancer Plasticity and Therapeutic Response.
复制标题
LKB1 失活会引发氧化还原失衡，从而调节非小细胞肺癌的可塑性和治疗反应。
DOI：
10.1016/j.ccell.2015.04.001
复制
发表时间：
2015-05-11
期刊：
影响因子：
50.3
通讯作者：
Ji H
中科院分区：
文献类型：
--
作者：
Li F;Han X;Li F;Wang R;Wang H;Gao Y;Wang X;Fang Z;Zhang W;Yao S;Tong X;Wang Y;Feng Y;Sun Y;Li Y;Wong KK;Zhai Q;Chen H;Ji H
LKB1 同时调节细胞生长和能量代谢。目前仍不清楚 LKB1 失活如何协调非小细胞肺癌（NSCLC）的肿瘤进展与代谢适应。在 KrasG12D;Lkb1lox/lox （KL）小鼠模型中，我们发现了肺腺癌（ADC）和鳞癌（SCC）中不同的活性氧（ROS）水平。ROS 可调节 ADC 向 SCC 的转分化（AST）。此外，磷酸戊糖通路失调和脂肪酸氧化受损共同导致了氧化还原失衡，并在功能上影响了 AST。在 LKB1 失活的人类 NSCLC 中也存在类似的肿瘤和氧化还原异质性。在新陈代谢压力的临床前试验中，某些 KL ADC 可通过鳞状突变产生耐药性。这项研究揭示了肿瘤可塑性的关键氧化还原控制，这可能会影响 NSCLC 的治疗反应。
LKB1 regulates both cell growth and energy metabolism. It remains unclear how LKB1 inactivation coordinates tumor progression with metabolic adaptation in non-small cell lung cancer (NSCLC). Here in KrasG12D;Lkb1lox/lox (KL) mouse model, we reveal differential reactive oxygen species (ROS) levels in lung adenocarcinoma (ADC) and squamous cell carcinoma (SCC). ROS can modulate ADC-to-SCC transdifferentiation (AST). Further, pentose phosphate pathway deregulation and impaired fatty acid oxidation collectively contribute to the redox imbalance and functionally affect AST. Similar tumor and redox heterogeneity also exist in human NSCLC with LKB1 inactivation. In preclinical trials toward metabolic stress, certain KL ADC can develop drug resistance through squamous transdifferentiation. This study uncovers critical redox control of tumor plasticity that may affect therapeutic response in NSCLC.