Deciphering and targeting the metabolic control of lung cancer de-differentiation.

肺癌（LC）最致命的特征是化疗耐药和转移性传播。在许多情况下，这两种情况都归因于细胞的存在，这些细胞是由去分化过程驱动的，比如上皮细胞到间充质细胞的转化（EMT）和癌症干细胞（CSC）程序，这可以促进临床复发。然而，到目前为止，还没有批准的药物可以减少或预防LC中EMT/CSC的发生。最近，我们的实验室发现一些代谢途径可以通过驱动EMT/CSC在癌细胞去分化和促进LC侵袭性中发挥强大的调节作用。这使我们推测存在一个更广泛的代谢基因网络，具有类似的活动，我们建议识别，调查和目标。事实上，采用无偏倚的全基因组转录组学分析，我们已经确定了与EMT最密切相关的代谢基因列表，我们的目标是1)在体外培养细胞中验证和功能研究，2)在LC患者的组织中量化，以及3)靶向可用的特定抑制剂。识别控制去分化过程的代谢途径可能在药物重新定位领域具有高度影响，因为与目前已知的EMT效应物和介质相比，几种代谢酶抑制剂已经在临床应用于非肿瘤相关疾病的治疗。因此，本提案的发现将为新的基于代谢的治疗策略提供基本原理，以减少侵袭性LC的破坏性影响。

The most lethal features of lung cancer (LC) are chemo-resistance and metastatic dissemination. In many cases, both are attributed to the presence of cells driven by de-differentiation processes like the epithelial-to-mesenchymal transition (EMT) and the cancer stem cell (CSC) program, which can foster a clinical relapse. However, to date there are no approved drugs reducing or preventing the occurrence of EMT/CSC in LC. Recently, our lab showed that some metabolic pathways can exert a powerful regulatory role in cancer cell de-differentiation and promote LC aggressiveness by driving EMT/CSC. This led us to speculate the existence of a broader network of metabolic genes with a similar activity, which we propose to identify, to investigate and to target. In fact, employing an unbiased whole-genome transcriptomic analysis, we already identified a list of metabolism genes most strongly correlating with EMT, which we aim 1) to validate and functionally investigate in cultured cells in vitro, 2) to quantify in tissues from LC patients, and 3) to target with available specific inhibitors. Identifying the metabolic pathways controlling de-differentiation processes could be highly impactful in the field of drug repositioning because, in contrast to currently known EMT effectors and mediators, several inhibitors for metabolism enzymes are already in clinical use for the treatment of not tumor-related diseases. The findings of the present proposal therefore will provide the rationale for novel metabolism-based therapeutic strategies to reduce the devastating effects of aggressive LC.