The integration of genomics -gene variations-, proteomics -abundance of proteins- and phosphoproteomics -proteins’ activation state- offers for the first time a specific view of how genetic alterations of cancer genes pave the way to cell malignancy. In a set of four publications at the topmost research journal “Cell” and its cancer-focused outlet “Cancer Cell”, researchers from the Clinical Proteomic Tumor Analysis Consortium (CPTAC) describe how DNA alterations in cancer driver genes translate into specific malfunctions in the cell’s machinery, leading to its oncogenic transformation and related outcomes. Dr. Eduard Porta, leader of the Cancer Immunogenomics lab at the Josep Carreras Leukaemia Research Institute, a CERCA center of the Catalan Government, signs two of the papers published today, as coauthor.
Cancer cells behave very badly. For decades, scientists have been trying to understand the whys and hows of this behavior and described thousands of DNA alterations affecting key genes contributing to cancer onset and progression. The rationale was that those cancer genes translated into proteins controlling important aspects of the inner working of the cell that, when altered, could trigger the Hallmarks of Cancer: the tipping points a cell must undergo to become a cancer cell. But cells are much more complicated than genes producing proteins. That’s why the CPTAC consortium moved from genomics to functional proteomics and compared 1065 genomes from 10 different cancer types, to find what is common across all of them in terms of mutations, gene expression and protein interactions. Their findings will set the foundation for the deep understanding of cancer in the coming years and help develop new therapeutic strategies based on the functional havoc inside cancer cells.
Comparing cancer cells with closely related non-cancerous cells from the same patients, researchers reported DNA mutations with significant effects on 59 genes, common to all cancer types. A fine-detailed analysis showed that many alterations affected the activity of those genes, either increasing or decreasing the abundance of its products (RNA or proteins). In a second paper at “Cancer Cell”, Porta and colleagues found that epigenetic alterations were also affecting gene activity with the same results. As expected, genes known for suppressing tumor progression (aka tumor suppressor genes) tended to be less active, while genes known to promote cancer progression (aka oncogenes) tended to be overactivated. The identification of cancer genes is of utmost importance now that molecular diagnosis is becoming widespread around the world, but there is a long way from gene activity to its functional consequences, which are the ultimate responsible for the actual symptoms and towards which drugs are targeted. That’s why the team of researchers went further and analyzed how mutations in cancer genes impacted the cell’s inner workings mechanistically.
In the paper, they reported how different protein abundance in cancer cells rewire protein-protein networks, triggering cancer-promoting cellular programs. Also, mutations can affect important sites in the protein, either abolishing its capacity to bind with its partners or being correctly activated, impairing the formation of the large protein networks as well. These results stress the importance of proteomics in cancer research to understand the consequences beyond mutation or epigenetic alteration.
The amount of data analyzed is so large, that the team could explore the far-reaching effects of defective proteins, way beyond the immediate interactions. Many proteins play roles in several cellular systems, and its presence or absence may affect a broad range of cellular functions. In general, mutations in many cancer-driver genes had very similar consequences, suggesting that they condensate into fewer cellular programs. However, some showed incompatible alternatives, that could be exploited therapeutically in the future. Some of the tumors in the sample were reported to have higher infiltration of the immune system than others. The researchers wondered whether genetic alterations in cancer drivers could cause the formation of aberrant proteins -neoantigens- that could awake the immune system. Their results confirmed a strong correlation between mutation and immune system infiltration, especially for a few sets of highly abundant cancer-driver proteins, and this could impact therapeutical advice in patients with similar tumors.
Overall, the findings of the research team advice for a most active implementation of functional proteomics and proteogenomic panels in the clinical practice, able to shed light into the functional aspects of a given tumor, beyond just its genetic alterations. Functional misbehaviors within cancer cells might be important not only for the generation of a new wave of anti-cancer drugs, but also to select the best treatment option in personalized medicine.