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性和转移性扩散。在许多情况下，两者都归因于由去分化过程驱动的细胞的存在，如上皮细胞向间充质细胞转化（EMT）和癌症干细胞（CSC）程序，这可能会促进临床复发。然而，到目前为止，还没有批准的药物减少或预防LC中EMT/CSC的发生。最近，我们的实验室表明，一些代谢途径可以在癌细胞去分化中发挥强大的调节作用，并通过驱动EMT/CSC来促进LC的侵袭性。这使我们推测存在一个更广泛的代谢基因网络，具有类似的活性，我们建议识别，调查和靶向。事实上，采用无偏的全基因组转录组学分析，我们已经确定了一系列与EMT最密切相关的代谢基因，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患者的组织中定量，3）用可用的特异性抑制剂靶向。鉴定控制去分化过程的代谢途径在药物重新定位领域可能是非常有影响力的，因为与目前已知的EMT效应物和介体相比，代谢酶的几种抑制剂已经在临床上用于治疗非肿瘤相关疾病。因此，本提案的发现将为新的基于代谢的治疗策略提供理论基础，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.