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

解读和靶向肺癌去分化的代谢控制。

• 批准号: 411725691
• 负责人: Dr. Paolo Ceppi
• 金额: --
• 依托单位: Department of Biochemistry and Molecular Biology
• 依托单位国家: 德国
• 项目类别: Research Grants
• 财政年份: 2018
• 资助国家: 德国
• 起止时间: 2017-12-31 至 2022-12-31
• 项目状态: 已结题
• 来源: https://gepris.dfg.de/gepris/projekt/411725691?language=en
• 关键词: Deciphering; targeting; metabolic; control; lung

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.

肺癌（LC）最致命的特征是化疗耐药性和转移性播散。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，例如上皮间质转化（EMT）和癌症干细胞（CSC）程序，这可能会促进临床复发。然而，迄今为止，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 促进 LC 侵袭性。这导致我们推测存在更广泛的具有类似活性的代谢基因网络，我们建议对其进行识别、研究和瞄准。事实上，通过无偏倚的全基因组转录组分析，我们已经确定了一系列与 EMT 密切相关的代谢基因，我们的目标是 1) 在体外培养细胞中进行验证和功能研究，2) 在 LC 患者的组织中进行定量，3) 以可用的特异性抑制剂为目标。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产生巨大影响，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上用于治疗非肿瘤相关疾病。因此，本提案的研究结果将为新型基于代谢的治疗策略提供理论依据，以减少侵袭性LC的破坏性影响。