Studying the selective role of autophagy in cancer
The goal of this project is to characterize the protective role of selective autophagy in human cancers, with the potential to develop novel therapeutic strategies in oncology. Defects in selective autophagy have been linked to tumorigenesis. The underlying mechanism has been proposed to be accumulation of aberrant proteins and organelles that drive radical oxygen species (ROS) production and result in persistent DNA damage. On the other hand, it is expected that cancer cells are dependent on selective autophagy for their survival due to progressive accumulation of genetic aberrations that drive production of misfolded proteins, protein aggregates and damaged organelles. Inability to clear cell junk should eventually result in cell demise, especially if a damage-inducing second drug already affects the cell. For therapies targeting autophagy, it is thus essential to assess the status of selective autophagy in cancer cells and patient-derived tumour material. The ESR will establish methods for purification of autophagosomes from cells and tissues and use these preparations to measure the levels of selective autophagy receptors (such as p62/SQSTM1, NBR1, etc.), ubiquitin and mitochondria before and after experimental manipulation of the selective autophagy, using small molecule or genetic tools. A proteomic approach will be employed to assess what additional cargo proteins are upregulated under the conditions when selective autophagy is inhibited. It is expected that multiple cancer-related, mutant proteins will be detected. Eventually, the effect of selective autophagy inhibition on cancer cell proliferation, migration and other hallmarks will be tested. Once the therapeutic concept has been demonstrated in cell culture, the ESR will perform in vivo experiments in xenograft models. Xenografts of different tumour cell lines in immunedeficient mice will initially be treated with autophagy inhibitors to assess how selective autophagy disruption affects their growth. Key target organs that the ESR will study to explore the potential of selective autophagy inhibitors in cancer therapy are the CNS, the muscles, the intestine and the liver, in which protein and organelle turnover by autophagy has been well described.