The dark proteome

Recent data indicate that cancer cells express proteins that are not derived from known open reading frames as well as proteins with alterations in amino acid sequences without corresponding DNA mutations. The origins of this ‘dark proteome’ remain elusive.

This challenge aims to define the mechanisms underlying the induction of these dark proteome products and understand their relationship with the oncogenic state of the cancer cell. It is also an opportunity to use them as therapeutic targets and understand whether the dark proteome is a source of non-mutated tumour-selective antigens and synthetic lethalities and determine whether these products can be targeted by immunologic or small molecule-based therapies that could be adapted to become ‘off the shelf’ treatments.

The focus of the challenge is on understanding the mechanisms giving rise to non-standard protein products (the dark proteome) and their impact on cancer. 

Current examples of the dark proteome (including many so-called microproteins) may be the tip of the iceberg. More work is needed to understand how these proteins are generated and to elucidate the role that they play in oncogenesis. A key question could be whether these products give rise to non-mutated antigens and whether they are universally expressed between individuals and across tumour types. Dark proteome products may be immunogenic, but it is unclear if they undergo the same immuno-editing as conventional antigens.

Similarly, understanding how the dark proteome functions in tumours could then be applied to the selective disadvantage of the tumour cell or to the advantage of the immune system.

Addressing this challenge may require integrating fields such as but not limited to immunology, cell biology, genetics, RNA and protein biology, mass spectrometry, synthetic and analytical chemistry as well as oncology.

Note: Applications that focus on non-coding RNAs, RNA editing/ mutations and retroelements that do not produce a protein product as well as applications that focus on alterations in RNA splicing will not be considered responsive to this challenge. 

Proteins are essential building blocks of life, created using instructions from our DNA. Usually, when proteins behave differently in cancer, scientists can trace the cause back to mutations, errors or changes in the DNA code. However, scientists have recently discovered a mysterious group of proteins called the ‘dark proteome’. These unusual proteins are made from unknown genetic instructions, or have unexpected modifications that cannot be explained by changes to our DNA. Scientists don't yet fully understand where they come from or the role they play in cancer.

This Cancer Grand Challenge aims to shed light on how and why cancer cells make these unusual proteins and whether they can be targeted for new treatments. By understanding the dark proteome, scientists hope to find new weaknesses in cancer cells. This could lead to innovative therapies that either block these proteins or use them to help the immune system attack cancer. If successful, this research could lead to new treatments that work for different types of cancer, offering new hope for patients.