The article “Microproteins in cancer: identification, biological functions, and clinical implications” delves into the emerging field of microproteins and their role in cancer. These small proteins, newly recognized beyond the traditional 19,500 known protein-coding genes, are involved in various cancer mechanisms and may influence oncogenic processes. This discovery redefines some aspects of cancer biology and holds promise for new therapeutic approaches targeting these microproteins, which could improve cancer treatment and outcomes.
What are microproteins?
Microproteins are small proteins often under 100 amino acids in length. They are generally overlooked due to their size and limitations in detection methods. But microproteins are now recognised as key players in various biological processes, including cancer. They are encoded by short open reading frames (sORFs) in regions once considered “non-coding” like the untranslated regions of mRNAs and long non-coding RNAs and are promising targets for cancer immunotherapy.
They are rapidly degraded and generate peptides that are easily presented on MHC-I molecules making them potential candidates for vaccines and therapies. Targeting microprotein-protein interaction and engineering microproteins for stability and specificity are promising strategies in drug development.
The Impact of Microproteins on Cancer Cell Survival and Treatment Implications
Microproteins are highly recognised for their essential role in cancer cell survival and treatment potential. Advancements in genomic techniques identified their functions and genomic alterations can lead to the production of new oncogenic microproteins or upregulation of existing ones leading to tumour development. These small proteins are selectively activated in cancer cells and often influenced by dysregulated RNA translation mechanisms and oncogenic signalling pathways.
Therapeutically, there are different strategies – (i) Directly targeting oncogenic microproteins can inhibit cancer cell proliferation, (ii) Disrupting microprotein-protein interaction could further weaken cancer cell resilience, (iii) Modulating their expression levels through delivery methods like viral vectors or antisense oligonucleotides, also presents as a potential treatment route, (iv) Vaccines targeting specific peptides could also be personalised based on a patient’s unique profile, enhancing treatment precision.
They are particularly valuable for cancer immunotherapy as non-mutational neoantigens. Their instability and efficient MHC-I peptide presentation make them visible to the immune system, ideal for therapies such as T-cell receptor (TCR) therapy and personalised cancer vaccines targeting specific tumour peptides. If engineered for stability, specificity and potency, microproteins themselves could serve as therapeutic agents. Using AI-driven design could help optimise them for clinical application.
Current Challenges in Microprotein Detection and Recent Advancements with Genomics
The fields of genomics and proteomics are progressing and are shedding light on microproteins and their role in cancer development, although they are difficult to detect. Mass Spectroscopy (MS) is the main microprotein detection technique, but their small size and instability makes the process complex. Although scientists have already come up with new methods to improve accuracy, there is still a need for more sophisticated instruments which will enable them to verify the data at the protein level.
Genomics techniques such as (i) ribosome profiling indicating which mRNA sequences are actively being translated into proteins, (ii) Bioinformatic analysis, which uses various computational techniques to predict the presence of sORF, helped identifying the presence of microproteins. (iii) CRISPR technology can be used to study their functions. However, CRISPR is restricted to cell proliferation and marker gene expression and to address this drawback (iv) single-cell RNA sequencing has been combined with CRISPR screening to provide more detailed information about gene function at the individual cell level.
Together, genomics and proteomics will help uncover regions coding for microproteins, their quantification and role in cancer cell survival. This could mean personalized therapies based on an individual’s genetic makeup, thus accelerating a more positive response to cancer treatment. Despite these advancements, validating microproteins at protein level remains a challenge and further technological advancements are required.