Grant Number:	1OT2CA320059-01 Interpret this number
Primary Investigator:	Prensner, John
Organization:	University Of Michigan At Ann Arbor
Project Title:	Illumine
Fiscal Year:	2026

Abstract Cells produce a previously under-appreciated class of non-standard proteins collectively termed the dark proteome that are not encoded by known open reading frames or explained by DNA mutations. The biological origins, regulation, and functional role of the dark proteome in normal tissues and cancer remain largely unknown. This challenge aims to uncover the mechanisms that give rise to dark proteome products and to define their connection to the oncogenic state. Team ILLUMINE led by Reuven Agami (Netherlands Cancer Institute) brings together interdisciplinary researchers with expertise in cancer biology, proteomics, genomics, chemistry, technology development, and clinical translation. The program will address four central questions: who the dark proteome players are, whether and how they are (dys)regulated in cancer, how they function, and how they can be therapeutically exploited. In addressing these questions, ILLUMINE will address major gaps in knowledge. Aim 1 will create a comprehensive map of dark proteome entities across several major cancer types and dissect potential stress-related mechanisms for their production. Aim 2 will codify a bench-to-bedside pre-clinical therapeutic development pipeline for immunotherapies from the dark proteome. Aim 3 will profile cell-based mechanisms of individual dark proteins in cancer biology, focusing on cell autonomous and non-cell autonomous mechanisms. Aim 4 will explore non-immunotherapy opportunities for targeting the dark proteome. Capitalizing on its unique expertise, the team plans to use and combine cutting-edge experimental approaches to uncover hidden layers of cancer cell biology. ILLUMINE aims to ultimately identify new tumor biology and treatment paradigms for patients based on the dark proteome.





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