Role of Autophagy and Lysosomes in Tumorigenesis and their Potential as Therapeutic Targets

Autophagy and Lysosomes in Tumorigenesis - Links with Intrinsic Anti-Cancer Barriers

While autophagy and lysosomal function have been suggested as barriers of tumor development, their ability to maintain cellular metabolism and to remove damaged organelles may improve the survival of cancer cells exposed to oncogenic stress and hostile tumor environment. Interestingly, oncogenes commonly evoke other cellular responses that initially counteract cell transformation or tumor progression, but when tumors overcome such barrier mechanisms and progress to a more aggressive stage, they may even depend on these pathways for their fitness, survival and therapy resistance. We will investigate the occurrence of defects or over-function of autophagy and lysosomes relative to tumor stage, and their functional relationships with anti-cancer barrier mechanisms. We will attempt to investigate the effect of malignant transformation on the composition (protein and lipid) of autophagosomes and lysosomes, and design and validate more reliable autophagy biomarkers.

Small Molecules that Modulate Autophagy-Lysosome and Proteasome Pathways

Based on the reciprocal control between the autophagy-lysosome network and other essential cellular processes, we are convinced that cancer therapy can be improved by drugs targeting this pathway. The therapeutic manipulation of the autophagy-lysosome pathway being the ultimate goal of the CARD Center, we will search for pharmacological inhibitors of the most cancer-relevant processes. Notably, inhibitors for many of the identified enzymes are already available and more are under development.

Autophagy and Lysosomes as Therapeutic Targets in Oncology

The ultimate goal of the CARD Center is to compile the obtained data regarding the complex regulation of the autophagy-lysosome pathway as well as its tumor-stage-dependent alterations and crosstalk with other cellular processes to define the most appropriate steps for therapeutic intervention via synthetic lethality. We will attempt to manipulate specific steps of autophagy and the regulators of lysosomal integrity by pharmaceutical and genetic means in cancer cell culture and mouse tumor models, individually and in combination with existing drugs targeting other pathways and standard-of-care treatments.