CARD - Status and Aims

Where is the CARD project now and what further should be achieved?

Status of the Field and Scientific Aims

Autophagy is a lysosome-dependent self-eating process responsible for the degradation of damaged and obsolete macromolecules and organelles, and subsequent recycling of amino acids, fatty acids and other basic compounds for cellular renovation and homeostasis. The low level of autophagy that maintains normal cellular homeostasis is rapidly enhanced by various internal and external cues. For instance, cells sense the lack of amino acids, glucose and ATP by distinct mechanisms and activate corresponding signaling pathways to trigger cytoprotective autophagy. On the other hand, when autophagy exceeds a certain threshold, autophagy is by-passed or lysosomal membrane integrity is sacrificed, cell death or cell cycle arrest may prevail. Accordingly, autophagy and lysosomes are linked to numerous human pathologies, including cancer and degenerative diseases.

Recent intensive research has led to the identification of mTORC1 and AMPK as key autophagy-regulating kinases, and characterization of products of 35 autophagy genes (ATGs) as mediators of autophagosome formation and maturation. Signaling pathways upstream and independent of mTORC1 and AMPK, arsenal of regulatory protein modifications, role of lipids and trafficking proteins, genetic and epigenetic regulation, selectivity towards specific cargoes, maintenance of lysosomal membrane integrity and crosstalk between autophagy and other cellular processes are, however, still largely unresolved. In spite of the growing number of clinical cancer trials targeting autophagy and lysosomes, even the question whether we should enhance or inhibit autophagy and lysosomal activity in cancer treatment has remained ambiguous. We propose that due to the extensive crosstalk between autophagy and other cellular processes, the therapeutic outcome of autophagy modulation depends on at which step autophagy is targeted, tumor stage and the therapeutic context. Our aim is to draw a global picture of autophagy-lysosome pathway regulation and its alterations in cancer to pinpoint the optimal events for therapeutic intervention.