ARCHIVED - NRC scientists map cancer pathways

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March 08, 2008— Ottawa, Ontario

NRC researchers have created the world's first "map" detailing all of the known cellular pathways by which proteins and genes interact to develop cancer in humans. The "human cancer signalling map" represents a powerful navigation tool to help scientists better understand the basic biology of cancer, and thereby guide the selection of new diagnosis and treatment methods for different cancers.

The map, which was published in December in the journal Molecular Systems Biology, captures 60 years' worth of accumulated scientific knowledge on all the genes known to have a role in different cancers as well as the "cellular signals" that regulate these genes by turning them "on" or "off" so they start or stop making the proteins they encode.

The human cancer signaling map shows more than 300 different proteins and nearly 900 signalling relationships among the genes that encode these proteins.
The human cancer signaling map shows more than 300 different proteins and nearly 900 signalling relationships among the genes that encode these proteins.

"To create our map, we searched through various databases that contain information on human cell signalling pathways," says Dr. Edwin Wang, project leader and a bioinformatics scientist at the NRC Biotechnology Research Institute (NRC-BRI) in Montréal. "We recruited students from two Chinese universities to manually record all of the signalling pathways involved in various biological processes. These pathways are connected and form a large network containing more than 1,600 proteins and 5,000 signalling relations."

"By mapping mutated genes that cause cancer onto the human cell signalling network, the cancer signalling map emerged," Dr. Wang continues. "The map shows more than 300 different proteins and nearly 900 signalling relationships among the genes that encode these proteins."

A primer on cell signalling

Human cells use sophisticated communication between proteins in order to initiate and maintain basic cellular functions such as growth, survival, proliferation and development. Due to "cross-talk" between signalling pathways, signalling proteins rarely operate in isolation, but rather through a large and complex network. As cell signalling can control cell growth and survival, any alterations of cellular signalling events, such as those that arise by mutations, can result in tumour development.

"Huge efforts have been made over the past few decades to illustrate cancer signalling. However, it has been a struggle to get clues to how cancer signalling is organized," says Dr. Maureen O'Connor-McCourt, a co-author of the study and scientific leader of NRC-BRI's Cancer Genomics project. "This map offers the first glimpse of a global view of the architecture of cancer signalling. The map shows well-known cancer signalling events as well as some potential cancer signalling events, which allows scientists to generate a number of testable hypotheses for future research."

"Traditionally, scientists have treated cellular signalling as linear pathways, like the avenues and roads of a city. We see the entire signalling map as a network or wiring diagram," says Dr. Wang. Based on the connections between different signalling pathways, the NRC team divided the signalling map into 12 protein communication modules, or signalling modules. "A protein communication module is like one area of the city, such as the downtown, which is a region of intersection of many different avenues and roads," he explains.

The large-scale sequencing of cancer genomes has shown that there is a lot of diversity and little overlap in terms of the different types of mutated genes among individual patients' tumours – even between tumours that originate from the same tissue. For example, a recent genome-wide sequencing of breast and colon cancer patient samples found that each patient has, on average, 11 different gene mutations.

Despite the complexity of these mutations, "the human cancer signalling map allows them to be classified into a few signalling modules, thus uncovering the underlying logic of cancer signalling," says Dr. Maria Jaramillo, a tumour cell biologist at NRC-BRI and co-author.

Among its potential applications, the cancer signalling map could help scientists determine which signalling pathways or modules are used by different types of cancers – in other words, which ones would make the best targets for drug development. It could also help researchers predict whether a drug or combination of drugs that impacts one gene will have similar effects on others, if it's known that the genes share signalling pathways or modules.

This map will be a work in progress as more and more scientific data becomes available, concludes Dr. Wang. "In future, we plan to create cancer signalling maps that focus on a particular type of cancer, such as breast cancer or lung cancer."

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