Over the past decades, cancer research has mapped genomes in extraordinary detail. But DNA is only the blueprint. Ultimately, it’s the proteins that shape tumor behavior, and growing evidence suggests that our current methods don’t capture all proteins.
Some are extremely small and unstable. Others arise when cancer cells are under stress, which occurs during chemotherapy or immunotherapy for example, and continue producing altered proteins while normal cells shut down. Some originate from genomic regions long thought to be silent. Others are fragments generated through unconventional degradation.
“These hidden proteins may represent a missing layer in our understanding of cancer,” says Reuven Agami, group leader at the NKI and Oncode Institute, who will lead ILLUMINE. “We have learned to read the genome very well and understand many of its mutations. But we suspect that we are still overlooking an entire layer of proteins that could fundamentally change how we think about tumor biology.”
Agami: “Like dark matter in the universe, the dark proteome is not directly visible with standard tools. We can only find what we are looking for. ILLUMINE will create a comprehensive atlas of the cancer dark proteome in difficult-to-treat cancer types.” Using cutting-edge experimental, computational, and proteomic approaches, the team will map where these proteins originate, how they are produced, and what roles they play in cancer cells.
Understanding the dark proteome may have profound implications for immunotherapy. “If we can identify dark antigens that are truly cancer-specific, we could open an entirely new universe of T-cell targets. That could be especially important for difficult-to-treat cancers, including certain pediatric cancers, pancreatic cancer, and other resistant tumor types” Agami explains.
The ambition goes beyond mapping. The consortium will also identify T-cell receptors capable of recognizing these dark antigens and explore whether they can be translated into therapeutic strategies. By integrating discovery-driven biology with translational immunology, ILLUMINE aims to bridge fundamental insight and future therapeutic innovation. Success would mean that the first clinical trials targeting dark antigens can be established within five years.
A key strength of the project lies in the NKI’s longstanding expertise in cellular stress responses. Cancer cells behave differently under stress than normal cells; continuing to produce proteins when healthy cells would stop. This stress-driven biology may be a major source of dark proteins.
“The NKI has been at the forefront of understanding how cancer cells respond to such stress,” says Agami. “That knowledge provides a unique foundation for exploring how hidden proteins are generated and why they might be cancer-specific.”
The selection by Cancer Grand Challenges, a global initiative co-founded by Cancer Research UK and the U.S. National Cancer Institute, recognizes both the scientific ambition of the project and the unique expertise at the NKI in uncovering previously unseen layers of gene regulation and protein expression.
The ILLUMINE consortium brings together researchers from the Netherlands, Israel, the United Kingdom, and the United States, combining expertise in cancer biology, immunology, proteomics, and computational science. What unites them is a shared fundamental scientific curiosity: to understand where these hidden proteins come from, why they are produced, what functions they perform, and how they might be exploited for therapeutic purposes.
The project does come with certain risks. Some dark proteins may prove less cancer-specific than we hoped. Others may be expressed at levels that are too low to translate into therapies. But only through careful investigation can we determine their true potential. “We are not starting with a drug,” Agami says. “We are starting with a fundamental biological question. If we are right, this could redefine what we consider targetable in cancer.”
Over the coming years, ILLUMINE will build an unprecedented resource for the global cancer research community: a reference atlas of the cancer dark proteome. While clinical applications may take time, the ambition is clear; to open an entirely new frontier in cancer biology and expand what is considered possible in cancer treatment.
ILLUMINE is funded by Cancer Research UK, the National Cancer Institute, Cancer Research Institute and KiKa (Children Cancer Free Foundation) through Cancer Grand Challenges. The team receiving support from KiKa (Children Cancer Free Foundation) reflects the shared commitment of international and Dutch partners to advancing fundamental cancer research.
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