For the first time, scientists have completed a detailed study of many of the proteins in bowel cancer cells. Research led by the Wellcome Trust Sanger Institute investigated the role proteins play in predicting how common mutations affect proteins in cancer cells, and whether such proteins are important in predicting the cancer’s response to treatment. The study used computational analysis designed in collaboration with researchers from EMBL-EBI.

Bowel cancer biology

The results, published in Cell Reports, give scientists a better picture of the cellular processes behind bowel cancer, and could enable researchers to predict which drugs would be effective in treating individual patients. 

In the UK alone, 110 people are diagnosed with bowel cancer every day. There are around 41,300 new cases of the disease each year, and it is the fourth most common cancer in the UK. 

Scientists have traditionally studied all of the cancer genes – the genome – and all of the RNA – the transcriptome – in this type of cancer. However, it is the proteome – all the proteins in a cell – that constitutes the main building blocks of cell machinery. 

The role proteins play

In the new study, scientists conducted a very deep, detailed study of the proteins in bowel cancer to investigate whether proteins play a role in predicting the effect of different drugs against the cancer. The researchers analysed 9000 proteins for each of 50 bowel cancer cell lines.

“This study is the first detailed characterisation of colorectal cancer cell lines,” explains Jyoti Choudhary of the Wellcome Trust Sanger Institute and the Institute of Cancer Research, London. “It is important to include the proteome in cancer research because proteins are the building blocks of life, and networks of proteins working together are known to drive fundamental processes in cancer. The proteome contains unique information on cell organisation and function.”

The team was able to construct co-ordinated networks of proteins that drive bowel cancer. Researchers used CRISPR-Cas9 to disrupt, or knock out, a single gene that encoded a key protein, and see the effects on the proteins in the rest of its network.

In the study, the team tested 265 existing anti-cancer drugs on the 50 bowel cancer cell lines. Details of the genome and transcriptome have previously been used to predict which drugs would work in particular cancer cases; however, the activity of some drugs could not be predicted. 

"The availability of such proteomics data-sets coupled with computational methods will further our understanding of key driver events in cancer,” commented Julio Saez-Rodriguez, Visiting Group Leader at EMBL-EBI.

“We know that cancer causes alterations in the genome,” explains Emanuel Gonçalves, PhD student at EMBL-EBI. “However, the data from this study suggests that many of these changes don’t transmit from genome to proteome, so they may have limited impact on the functioning of the cell.” 

By studying the proteome, the team could predict drug responses that were not explained by either genomics or transcriptomics. 

Unprecedented insight

“Combining the expertise of different groups allowed us to consider the genome and proteome together, which offers unprecedented insights,” adds Fatemeh Zamanzad Ghavidel, Postdoctoral Researcher at EMBL-EBI between the Brazma, Saez-Rodriguez and Stegle groups.

“This study is promising for bowel-cancer patients,” concludes Ultan McDermott of the Wellcome Trust Sanger Institute. “It confirms that this common cancer is actually composed of five different subtypes that may require different drug treatments and, surprisingly, suggests that proteins may be more predictive for drug sensitivity than we have previously thought. In the future, we may need to test the patient’s genome, transcriptome and proteome to fully predict their response to cancer drugs and stratify patients for clinical trials more effectively. We are moving away from one size fits all towards personalised medicine.”

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