12:00 Dr. Federico Lucantoni 

BCL2 proteins: master regulators of cell death or bioenergetics? Exploring the boundary between cell death and metabolism in cancer.

BCL2 family of proteins establish a complex interaction network among pro and anti-apoptotic members to regulate the mitochondrial membrane permeabilization (MOMP), a point of no-return in the commitment of cells to death. The accumulation of both pro and anti-apoptotic members drives cancer cells progression and therapeutic response. The complexity of the BCL2 interactome has posed a challenge in the prediction of cellular responses to genotoxic therapies.

To overcome this limitation, we have developed DR_MOMP (dose response mathematical outcome model predictor), a mathematical model based on the BCL2 protein expression and interactome. DR_MOMP calculates a single value that indicates the tumour’s sensitivity to mitochondrial apoptosis. This has been validated in cancer cell lines and patients’ samples.

In addition to cell death, BCL2 proteins have also a crucial role in metabolism modulation. By using single cell imaging approaches, we have demonstrated that BCL2 and BCL(X)L improve mitochondrial bioenergetics and dynamics. These non-canonical roles of BCL2 proteins are particularly relevant to understand the secondary effects that BCL2 inhibitors (now approved for the use in the clinical setting) might have on patients. Moreover, this has implications in the development of new combinatorial therapies to target cell death and metabolism.

Finally, our current work aims to decipher the behaviour of cancer cells in physiological conditions and to understand how metabolic rewiring influences drug response.