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

Project description

Proteosome structure and degradation landscape regulation in cancer

Proteasomes remove defective or obsolete proteins, playing a role in cell signalling and antigen presentation. Proteasomal degradation was implicated in tumour interaction with immunity, but a comprehensive analysis of significance in cancer is not complete. Researchers from the Weizmann Institute of Science in Israel developed proteasomal footprinting using mass spectrometry analysis of proteolytic peptides (MAPP) for capturing, isolation, and analysis of proteasome-cleaved peptides. The EU-funded Cancer_Deg project aims to further develop MAPP technology to uncover the critical role of degradation pathways in cancer. The objectives include the development of in vivo characterisation of proteasome composition and the degradation landscape in different cancers, the study of the mechanisms underlying tumour immunogenicity and response to immunotherapy, and the exploitation of inter-patient proteasome heterogeneity for translational purposes.


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.


Net EU contribution
€ 1 978 750,00
Herzl street 234
7610001 Rehovot

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Activity type
Higher or Secondary Education Establishments
Other funding
€ 0,00