Deciphering regulatory principles of proteasome heterogeneity and the degradation landscape in cancer

ongoing

Proteasome activity is crucial to removal of defective or obsolete proteins, cell signaling and antigen presentation. In cancer, proteasomal degradation was shown to play key roles in tumor growth, antigenicity and response to immunotherapy. Yet, comprehensive analysis of proteasome subunit composition and the degradation landscape in cancer has not been performed to date, rendering our understanding of inter-patient proteasome heterogeneity and proteasome-dependent mechanisms underlying tumor-immune interactions far from complete. Our novel, unbiased approach, MAPP, for MS Analysis of Proteasome-cleaved Peptides, is ideally suited to examine the missing link between cellular degradation and cancer immunity. We have already demonstrated its utility in identifying degradation events associated with inflammation, proteasome cleavage, substrate alterations and an anti-inflammatory role of the proteasome subunit PSME4, in lung cancer. We aim to capitalize on our powerful analytical methods, vast experience and preliminary data and develop further our cutting-edge technology, to shed light on the uncharted area of degradation pathways in cancer. We plan to: (1) Characterize both proteasome composition and the degradation landscape across cancer types and develop MAPP further to enable in vivo, tissue-specific, and proteasome-type-specific profiling. We strive to provide a near complete narrative of proteasome activity and distribution in tumors and their role in shaping tumor-immune interactions. (2) Study proteasome-dependent mechanisms underlying tumor immunogenicity and response to immunotherapy at the biochemical, cellular and physiological levels. (3) Exploit inter-patient proteasome heterogeneity for translational opportunities, in particular as an adjunct to current immunotherapies. Cancer_Deg will transform our understanding of proteasomal degradation in cancer, with important implications for numerous diseases, precision oncology and drug discovery.