Inside one of the most comprehensive human proteome atlases to date

Identifying a promising therapeutic target requires more than showing that a protein is involved in disease. Researchers must also understand where the target protein is expressed throughout the body, how its abundance changes across different tissues and whether targeting it could affect healthy cells.

In a study published in Nature, researchers describe one of the most comprehensive human proteome atlases to date, quantifying more than 13,600 proteins across almost every major human tissue and 25 common cancer types. By enabling protein expression to be compared across healthy, foetal, tumour and adjacent non-tumour tissues, the atlas provides a valuable resource for investigating disease biology, prioritising therapeutic targets and identifying opportunities for drug repurposing.

Why protein expression matters

Genomic and transcriptomic technologies have helped researchers identify genes and signalling pathways associated with disease. However, genes represent only part of the picture. Proteins carry out most cellular functions, acting as enzymes that catalyse chemical reactions, receptors that receive signals, transporters that move molecules and structural components that maintain tissues. They are also the molecules targeted by most medicines.

The proteins expressed by a cell depend on its function. Skeletal muscle, for example, produces proteins needed for contraction, while the liver is enriched with metabolic enzymes. Protein expression also changes throughout development, ageing and disease. In cancer, some proteins become more abundant while others are lost as tumours acquire new biological characteristics.

Understanding where proteins are expressed is therefore essential for drug discovery. A protein may appear to be an attractive therapeutic target because it is linked to disease, but if it is also abundant in healthy tissues, targeting it could increase the risk of unwanted effects. Researchers therefore consider not only whether a protein is associated with disease, but also where it is expressed throughout the body.

Improving therapeutic target selection

The atlas identified more than 1,700 tissue-enriched proteins, including hundreds that had not been reported in previous human proteome resources. Many of these newly identified proteins came from tissues that had received relatively little attention in earlier studies, expanding the range of proteins available for therapeutic investigation.

The resource also provides important biological context when evaluating potential targets. Proteins enriched in different tissues reflected the specialised functions of those organs, with synaptic signalling proteins concentrated in the brain, metabolic proteins in the liver, proteins involved in cardiac chamber development in the heart and proteins associated with lens development in the eye. Understanding these relationships can help researchers judge whether a protein is biologically plausible as a therapeutic target, rather than relying on disease association alone.

The cochlea illustrates this well. The atlas identified PANX3 as its most highly enriched protein, despite it previously being classified as ‘not detected’ in the Human Protein Atlas, suggesting that tissue-specific proteomic profiling can uncover potential targets that earlier resources missed.

Understanding how cancers differ

By comparing tumour samples with matched adjacent non-tumour tissue from more than 1,000 patients, the researchers identified almost 9,000 proteins whose abundance changed in cancer. Some of these changes were common across multiple tumour types, suggesting shared mechanisms of tumour development, while others were unique to individual cancers, reflecting differences in their biology and tissue of origin.

Some of these cancer-specific features only became apparent at the protein level. Gastrointestinal stromal tumours, for example, retained proteins associated with neuronal signalling, reflecting their origin from the interstitial cells of Cajal. Liver cancers, by contrast, showed widespread disruption of proteins involved in metabolism.

Predicting toxicity before clinical testing

The atlas also revealed links between tissue-specific protein expression and drug safety. The researchers identified more than 400 tissue-specific drug targets associated with almost 2,600 medicines. Comparing these targets with reported adverse effects showed why some medicines are linked to toxicity in particular organs.

One example was thyroid peroxidase, which is highly expressed in the thyroid. The protein was associated with reports of thyroid dysfunction linked to triclosan exposure, suggesting that tissue-level protein maps could provide additional context when assessing drug safety.

Supporting drug repurposing

The findings also pointed to opportunities for drug repurposing. Approved therapies for breast and ovarian cancer target proteins that were also overexpressed in endometrial cancer, suggesting they could be evaluated in another tumour type. Several of these strategies are already being tested in clinical trials.

The researchers also identified potential new therapeutic targets. By combining the proteomic data with drug sensitivity and CRISPR gene essentiality datasets, they identified proteins that were both highly expressed in tumours and more likely to respond to targeted therapies. 

A foundation for future discovery

No atlas can capture every aspect of human biology. The authors acknowledge several limitations, including that the normal tissue samples were predominantly obtained from older donors, which may have influenced the representation of some tissues. They also note that some tissue types required specialised preparation methods and that the relatively small number of patients within individual cancer types limited the assessment of inter-patient variability.

Even so, by analysing thousands of healthy and cancerous tissue samples using a consistent workflow, the atlas provides one of the most comprehensive maps of human protein expression to date.

As proteomic technologies continue to advance, comprehensive resources such as this are likely to become increasingly valuable for therapeutic target selection, safety assessment and understanding disease biology.