Cancer’s Fight Against Drugs May Reveal a Better Way to Fight Cancer

Scientists at Keck Graduate Institute (KGI) have taken a peek at the genome’s playbook and they are using it to discover how cancer overcomes chemotherapy and other treatments.

KGI postdoctoral fellow Biranchi Patra, KGI professor Animesh Ray, and former KGI professors David Galas, Chris Adami, and Alpan Raval are co-authors of a recent publication, “A genome wide dosage suppressor network reveals genomic robustness,” in the international scientific journal Nucleic Acids Research on Nov. 29, 2016 (doi: 10.1093/nar/gkw1148).

This publication is the capstone of a collaborative project funded by a grant from the National Science Foundation within the Frontiers in Integrative Biological Research program. The work involved a number of collaborators at KGI and other institutions.

The publication features 15 additional coauthors, some of whom were undergraduate, graduate, postdoctoral or visiting researchers at KGI. Several are professors at other institutions, including Nitin Baliga at Institute for Systems Biology, and Elizabeth Grayhack and Eric Phizicky from the University of Rochester’s School of Medicine. Patra is the joint first co-author along with Yoshiko Kon of University of Rochester. Galas, the principle investigator on the grant, was a co-founder of KGI and served as the school’s first chief academic officer and chancellor.

For more than a decade, scientists at KGI have had a passion for exploring the modularity of biological systems. Ray explains that through evolution the genome can arrange, re-arrange, use, and re-use genes much like plug and play computer engineering to overcome harmful mutations in other genes. This is referred to as genetic robustness.

“The publication explores how different organisms innovate and reorganize their functional gene modules to circumvent the effects of extreme or lethal perturbations,” Patra said.

The research team has been working with baker’s yeast, which is an effective model for learning about human biology.

“We tracked down the source of this robustness to a modular organization of genes,” Ray said. “This means that the way genes are organized in the genome generates an emergent property that surpasses the effects of some of their individual properties.”

Just like genes working together to suppress other “bad” genes, cancer cells exploit novel mechanisms to survive chemotherapy and radiotherapy.

“This ability of cancer cells to innovate and survive is a kind of robustness to changing environment,” Patra said.

Concepts derived from this work are currently being pursued in Ray’s KGI laboratory, now funded by Department of Defense. Ray and his team continue to explore how networks of genes suppress harmful mutations in other genes.

“One possibility is that the reason cancers are so difficult to cure is because cancers utilize this robustness property of the human genome,” Ray said. “Prompted by this line of thinking, we have embarked upon a study to investigate the extent of robustness of lung cancer cells when these cells are exposed to potentially lethal effects of an anticancer drug. By discovering how cancer cells can overcome the effects of this drug, we hope to be able to discover how robust the human genome really is.”

Other scientists and research centers are working with similar concepts. University of Toronto professor Charles Boone has pursued a study of how mutations in genes can overcome deleterious mutations in other genes. Due to the similarities of the two projects, Boone and his team were able to provide insights and materials that helped the KGI research team. Although their studies had different foci, the connection between the scientists was valuable.

“This is an example of interdisciplinary work by faculty members and students with very different specializations and training to come together to address an outstanding problem at the forefront of biology,” Ray said.

Much like the biological modularity they are studying, these scientists are each individual parts of a social network that organizes and reorganizes, each time discovering more about the power of genome robustness, which will one day translate into lifesaving technologies. Such collaborations are invaluable for current research into complexities of the genome.

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Notes: Adami is now a professor at Michigan State University while Galas serves as the principal scientist at the Pacific Northwest Diabetes Research Institute. Raval is research manager and data scientist at LinkedIn. Patra is now a technical consultant at Gilead Sciences Inc.