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

• Applicant: Dr. Paolo Ceppi
• Subject Area: Hematology, Oncology
• Term: from 2018 to 2023
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 411725691

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.

• DFG Programme: Research Grants
• International Connection: Denmark