Structural oncology and the secret life of cancer cells
According to the World Health Organization, nearly 10 million people die of cancer each year, and approximately 20 million are newly diagnosed. While the link between genetic mutations and cancer is well established in cancer research, dysfunctional proteins are the fundamental drivers of malignancies that disrupt cellular homeostasis.
To date, cancer prevention has centered on minimizing the damaging effects of gene mutations. There’s a growing movement in chemoprevention, however, to modulate the proteins that encode for these disrupted genes. For example, the BRCA1 protein is involved in tumor suppression as it contributes to the repair of damaged DNA. Individuals with limited BRCA1 functionality accumulate more genomic instability, leading to a higher likelihood of cancer induction. To fully understand how BRCA1 function breaks down, researchers need accurate molecular insights into the structures of these protein.
“When things go wrong inside cancer cells, what can we do about it?” asked Penn State University Prof. Deb Kelly during a recent Thermo Fisher Scientific webinar with Labroots about cancer research. “We’re developing new tools to see biology differently, and to create a new vision for how we think about diseases and treat them. We want to apply these tools to structural biology.”
Advances in oncology and cancer research enabled by cryo-electron microscopy
Cryo-electron microscopy (cryo-EM) describes a family of techniques, including single particle analysis and cryo-tomography, used to obtain high-resolution structural information for biological systems.
In cryo-EM, sample solutions are rapidly frozen, preventing the formation of crystalline ice and preserving the native structure of the specimens. In single particle analysis, this results in a suspension of individual proteins oriented at various random angles within the ice. A cryo-transmission electron microscope (cryo-TEM) is then used to image the proteins, generating thousands of 2D projections of the sample. These projections can then be recombined into a high-resolution 3D representation of the protein. With modern electron detectors and analysis software, atomic resolution is possible and increasingly more accessible.
Scientists now use cryo-EM to support cancer research, leading to the advancement of “structural oncology,” a new field that hopes to apply the principles of structural biology to the fight against cancer.
Prof. Kelly and the team at Penn State visualize cancer-related proteins, including BRCA1 and p53, to understand what structural changes lead to their malfunction. These insights can inform the development of highly targeted drug treatments.
Fundamentally, Prof. Kelly and team want to understand how problems with tumor suppressors lead to cancer, how it spreads throughout the body, and what treatments might stop this behavior.
“We grow cancer cells and extract the nuclear information from them. We then go through a series of biochemical experiments to get a pretty purified form of these proteins. Then we add these to microchips, or cryo-chips, image them inside the electron microscope, and do computational analysis on what their structures look like. This led us several years ago to the first cryo-EM structure, or even 3D reconstruction, of BRCA1 down to the binding partner BARD1.”
Ultimately, they hope to aid in the development of new molecular management plans and next generation therapies that are available beyond chemotherapy or radiation.
“We hope to make very specific treatments available that modify and treat these protein confirmations at different stages of prevention and treatment,” said Kelly. “I think this can all be accomplished by these new tools that we have to view structures and nanobiology differently.”
Other groups use cryo-EM to demystify the behavior of poorly understood therapeutic agents. Genentech recently investigated the structure of rituximab, a monoclonal antibody used in the treatment of various cancers. By visualizing this protein in complex with its cellular target, researchers were able to determine its exact mechanism of action, guiding future improvement and drug development.
The high-resolution analytical capabilities of cryo-EM are poised to revolutionize how researchers approach oncology, allowing targeted observation, analysis, and ultimately, treatment.
“I think having access to cryo-EM is essential if you’re doing anything in cell molecular biology,” said Kelly. “Find a colleague to work with who has a specialty in cryo-EM, and if you don’t have cryo-EM at your facility, there are certain outreaches by NIH that have made larger cryo-EM access facilities available across the country.”
To learn more about how cryo-electron microscopy is being used in cutting-edge structural oncology research, watch the recent webinar by Prof. Deb Kelley of Penn State University, Structural Oncology – Fighting Cancer with Cryo-EM., and read our eBook, Understanding the Complexity of Cancer with Cryo-EM.
Alex Ilitchev, PhD, is a Lead Scientific Editor at Thermo Fisher Scientific.