Metabolic determinants of stemness in Pancreatic Ductal Adenocarcinoma
For the last years it has become apparent that cancer cells within a tumor are extremely heterogeneous; not only genetic and epigenetically, but also in terms of differentiation state and functionality. Similar to haematological malignancies and other solid tumours, cells with tumour-initiating properties or Cancer Stem Cells (CSCs) represent the major source of chemoresistance, relapse and metastases in Pancreatic Ductal Adenocarcinoma (PDAC). We recently discovered that while differentiated pancreatic cancer cells rely on glycolysis, pancreatic CSCs are addicted to oxidative phosphorylation in order to maintain their stemness and functionality. This addiction makes them particularly sensitive to drugs targeting mitochondrial metabolism, such as the antidiabetic compound metformin. Although the recent use of metformin in PDAC patients revealed the rapid onset of resistance, we provided proof-of-concept for the success of metabolic targeting of pancreatic CSCs using combination therapies. In this talk, I will discuss our recent results exploring different aspects of pancreatic CSC metabolism in order to identify new vulnerabilities amenable to pharmacological inhibition.