Ulrich Baxa and Natalia De Val Alda look at the Titan Krios microscope at the Frederick National Laboratory.
Published:
7/24/2018

FREDERICK, Md. -- Nearly one-third of all human cancers are driven by mutations in RAS genes, including almost all pancreatic cancers. Treating these cancers has puzzled scientists for decades, and many RAS proteins are considered virtually undruggable. 

The Frederick National Laboratory for Cancer Research is attacking this longstanding problem from several new vantage points. It’s leading a multidisciplinary effort to address some of the most difficult questions in RAS biology, including trying to better understand RAS interaction with membranes. Several recently launched collaborations are aimed at this mission. 

Collaboration with Oak Ridge National Laboratory

A significant part of this effort was launched earlier this year through a collaboration with Oak Ridge National Laboratory with the purpose of studying large, multi-subunit proteins that may have disordered regions such as the neurofibromatosis type 1 (NF1) protein. A protein subunit is a single protein molecule that assembles with other molecules to form a protein complex. Disordered proteins lack a fixed or ordered three-dimensional structure, and scientists have yet to find a way to sufficiently study their properties.  

NF1 is a large protein with many characteristics. Mutations in NF1 are associated with many diseases, including neurofibromatosis, a genetic disorder that causes tumors to form in the nervous system.

Mutations in NF1 are of interest to RAS pathway biologists because they result in “RASopathies,” a group of developmental syndromes caused by mutations in genes that encode components or regulators of the RAS pathway, a signaling cascade that regulates cell growth and function. 

For the collaboration, Oak Ridge National Laboratory is using small angle neutron scattering, an experimental technique that shoots neutrons at proteins to produce high resolution images of proteins and complexes. Neutrons are scattered by atoms in proteins making it possible to study the proteins’ shape or 3D envelope. 

In parallel, Frederick National Laboratory scientists are producing cryo-electron microscopy images of components of those same proteins using frozen, hydrated specimens to produce a good estimate of subunit structures. The images are produced at molecular resolution without the need for dyes or fixatives. The resulting information will then be used to guide molecular dynamic computer simulations of disordered protein regions at Oak Ridge. Data from the small angle neutron scattering, cryo-electron microscopy, and molecular dynamic simulations are then combined to generate new models for the structure NF1.

Joint Design of Advanced Computing Solutions for Cancer (JDACS4C)

The Frederick National Laboratory and National Cancer Institute are part of JDACS4C, an ongoing collaboration among several national laboratories supported by the Department of Energy aimed at applying large-scale computational approaches to address challenges in cancer biology. One of its pilot programs has the goal of better understanding the mechanisms and dynamics of RAS interaction with the plasma membrane. 

The collaboration uses predictive computational modeling, machine learning, and cryo-electron microscopy, among many other disciplines, to contribute to the scientific understanding of RAS membrane biology.

“Understanding the dynamics of normal and oncogenic RAS proteins in the context of the plasma membrane at the molecular level is a challenge that requires multidisciplinary insights from microscopy, molecular, and structural biologists, physicists, biochemists, bioengineer, data scientists, and computational experts,” wrote Dwight Nissley, Ph.D., director of the Frederick National Laboratory’s Cancer Research Technology Program in a recent blog post about the collaboration.

International Partnerships

Through a collaboration that began last year with the Weizmann Institute of Science in Israel, the Frederick National Laboratory is using its expertise in structural biology and biochemistry in combination with the Weizmann Institute’s computational screening methods to identify small molecules that bind to or influence the activity of KRAS4b, a protein that is frequently mutated in pancreatic, colon, and lung cancers. The results could help identify new therapeutic opportunities to target these types of cancers.

The Frederick National Laboratory also launched a partnership last year with the Cancer Research UK Beatson Institute in Glasgow, Scotland to develop gold-standard tests to analyze candidate drugs against RAS. 

There are many other examples of how Frederick National Laboratory researchers are contributing to the study of RAS interaction with membranes. The national laboratory is uniquely positioned to partner with outside organizations to leverage new ideas and technologies in combatting RAS. Learn more about the latest information regarding the RAS Initiative. Read more about partnership opportunities with the Frederick National Laboratory. 

By Max Cole, staff writer

Image: Ulrich Baxa, Ph.D., (left) with Natalia De Val Alda Ph.D., (right) with the Titan Krios transmission electron microscope at the Frederick National Laboratory.  

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