By charting more than 13,000 proteins across healthy tissue and cancer, this study provides powerful new guides to development, tumor biology, drug safety, and future therapeutic targets.
Research: Spatial distribution of the proteome in the human body and cancer. Image credit: cybermagician / Shutterstock
In a recent study published in the journal natureresearchers have developed one of the most comprehensive maps of protein expression to improve our understanding of the biological mechanisms that drive health and disease. They measured the abundance of more than 13,000 proteins across more than 2,800 samples using data-independent acquisition mass spectrometry (DIA-MS). This atlas provides detailed characterization of proteins, key functional molecules within cells, across normal and cancer tissues.
Diseases and cancers alter cellular function through molecular changes that affect protein activity. Identifying these molecular changes in constituent proteins can help scientists develop more personalized treatments. Existing repositories contain protein expression data from tumors. Several research initiatives are extending these resources to include genetic and transcriptomic data from adjacent normal tissues. Scientists are currently exploring different methods to reliably and simultaneously quantify thousands of proteins across tissue types in healthy and tumor samples.
About research
In this study, the researchers provided a detailed quantitative map of human proteins. They performed DIA-MS to profile 13,609 proteins in 2,856 samples from nine postmortem adult donors, nine postmortem fetal donors, eight healthy individuals, and 1,015 cancer patients.
The research team used t-SNE visualization to investigate whether fetal, tumor, paired non-tumor, and healthy adult samples followed regular patterns. We then performed trajectory analysis to quantify the sequence by assigning a “pseudo-time” score to each sample. They also noted that brain and liver tumors and paired non-tumor samples deviated from this overall pattern. We also performed unsupervised clustering to group proteins with similar expression patterns across samples.
Researchers have identified proteins that are abundant in specific tissues. We then associated them with the special features of those tissues. The research team calculated Euclidean distances to assess similarities and differences between protein profiles. They used Human Protein Atlas (HPA) criteria to identify single tissues, groups of related tissues, proteins that are ubiquitous but particularly enriched in specific tissues, and proteins with unclear patterns.
The researchers then compared the proteins that were particularly abundant in certain tissues to known drug targets listed in DrugBank. This helped identify organs susceptible to drug-related toxicity. They also analyzed the dataset to identify changes in cancer-associated proteins and potential drug targets. They also analyzed drug sensitivity data and clustered regularly interspaced short palindromic repeat (CRISPR) gene essentiality data to assess the responsiveness of cancer cells to the identified drugs and gene knockouts.
result
The researchers analyzed proteins in samples representing 58 healthy adult tissues, 251 tissue subtypes, 22 fetal tissues, and 25 different cancers. Although protein profiles vary by tissue and sample type, repeated analyzes of the same samples yielded nearly similar results. In protein profiling, fetal tissue, tumor tissue, adjacent non-tumor tissue, and normal adult tissue were placed along a continuum reflecting increasing tissue differentiation, with brain and liver samples being notable exceptions.
Brain tissues across fetal, tumor, paired non-tumor, and normal adult conditions exhibited relatively stable protein profiles with few developmental changes. Liver tissue showed much greater changes, which the authors associated with adaptive plasticity of the liver. Proteins involved in ribonucleic acid (RNA) processing are most abundant in fetal tissues, whereas proteins associated with antibody-based immunity are enriched in adult tissues.
Tissues with specialized biological functions, such as the semicircular canals and cochlea, formed distinct molecular clusters, while functionally related tissues, such as the brain, spinal cord, and peripheral nerves, formed close clusters. The research team identified 832 proteins that were uniquely enriched in this dataset across 36 tissues that overlapped with the HPA data. For example, they detected particularly high levels of pannexin 3 (PANX3) in the cochlea and confirmed its presence using a synthesized PANX3 peptide.
This analysis linked 2,598 drugs to 402 proteins that were particularly abundant in specific tissues. The liver contained most of these targets. Cytochrome P450 2C8 (CYP2C8), a liver-enriched enzyme involved in drug metabolism, was the target of 302 drugs. The researchers emphasized that gemfibrozil is a strong CYP2C8 inhibitor, which can increase the concentration of co-administered drugs and increase the risk of side effects. Exposure to triclosan is associated with changes in thyroid function, and triclosan targets thyroid peroxidase, an enzyme essential for thyroid hormone production.
The research team identified 8,940 differentially expressed proteins (DEPs) across 25 cancer types, of which 2,878 were cancer type specific. Testicular cancers exhibit increased expression of tissue-specific proteins, suggesting that these tumors may utilize unique germ cell proliferation programs. The researchers also screened for 77 upregulated DEPs that were common in tumors targeted by 36 biomolecular drugs (mainly receptor tyrosine kinase inhibitors) evaluated in 2,084 clinical trials. The findings suggest that Trodelvy, an antibody-drug conjugate approved for triple-negative breast cancer, may be investigated for endometrial cancer, as both trophoblast cell surface antigen 2 (TROP2) and DNA topoisomerase 1 (TOP1) are upregulated in endometrial cancer. They also identified potential novel targets, such as TYROBP, which could be studied as a common antibody-drug conjugate target, although bone marrow expression requires toxicity evaluation.
conclusion
This discovery provides a comprehensive human protein atlas across healthy and tumor tissues to improve our understanding of tumor pathophysiology. This dataset could help advance research in human development, tissue biology, and drug discovery by elucidating health- and disease-specific changes in fetal and adult tissues. In future studies, researchers should include larger samples of individuals across different ages and tumor types to validate the findings.
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