Dissection of Bioenergetic Plasticity of Tumors

ongoing

Tumors reprogram their metabolism to fuel rapid growth. Glycolysis and oxidative phosphorylation “OXPHOS” are the main energy-producing pathways. For decades, metabolic reprogramming of tumors was perceived as only increased glycolysis (Warburg effect). This dogma has recently been revised as we started to realize the importance of OXPHOS in tumor metabolism. We are now entering a new era as metabolomics studies show that tumor metabolism is more heterogeneous than initially assumed. In the preparatory phase of this proposal, using an integrated transcriptional and metabolic profiling, a panel of cancer cell lines was first classified according to the bioenergetic pathway they predominantly utilize (glycolysis or OXPHOS). Second, the response of glycolytic and OXPHOS-dependent cells to the inhibition of their wired bioenergetic program was assessed. My findings show that regardless of their dependency at baseline, cancer cells can be collectively categorized according to their adaptability into “bioenergetically-committed” to one of the two pathways or “bioenergetically-plastic” cells which are able to switch from one to the other upon metabolic challenges. This proposal uses an integrated system approach to dissect the molecular signature, regulation and implications of bioenergetic plasticity. We will answer three key questions: 1-Why some cancer cells are bioenergetically-plastic while others are committed? What are the differences in metabolic machineries and oncogenic switches between both? 2-How heterogeneous tumor cell subpopulations are in terms of bioenergetic plasticity? Does metabolic crosstalk contribute to bioenergetic plasticity of tumors? 3-What are the implications of bioenergetic plasticity in drug resistance and metastasis and finally how to design approaches to target this plasticity? Only handful drugs targeting tumor energetics have made it to clinical use. ONco-Energetics_OFF has a realistic and immediate translational potential.