Summary: By making two distinct modifications to a single signaling protein, researchers were able to both suppress lung cancer growth and stimulate neuronal regeneration.
Source: Stanford
Overview
Our lungs, bones, blood vessels and many other vital organs are composed of cells that communicate through protein messengers called ligands. These ligands bind to receptors on cell surfaces and control essential biological processes. When those molecular messages are disrupted or misdirected, disease can follow. A team led by Stanford bioengineer Jennifer Cochran has now demonstrated that precise engineering of a single ligand can produce two very different therapeutic outcomes: promoting neurogenesis in injured neurons or blocking lung tumor growth.
The experiments, described in the Proceedings of the National Academy of Sciences (PNAS), were carried out on rat and human cells and in mouse models of disease. While still early-stage and not yet tested in humans, the findings illustrate how molecular engineering of ligand–receptor systems can be used to design targeted therapies for cancer, neurodegeneration and other disorders.
Engineering ligands to change cellular signals
Cochran’s laboratory focuses on how ligands and receptors interact to transmit messages into cells, and how those interactions can be tuned to create therapeutic proteins. Shape and sequence matter: ligands and receptors are linear chains of amino acids folded into specific three-dimensional structures. When a ligand’s shape matches a receptor, it binds like a key fitting a lock and triggers downstream signaling.
Using advanced molecular engineering techniques, the researchers alter the amino acid sequence of a ligand to generate many variants. They then screen those variants to find molecules that either enhance signaling—so-called superagonists—or block signaling as antagonists. A superagonist can amplify beneficial signals, for instance encouraging cell growth or regeneration, while an antagonist can prevent signals that drive harmful processes such as tumor proliferation.
Two outcomes from modifications to one ligand
Building on earlier work from Cochran and collaborators that used engineered receptor proteins to halt lung tumor growth in rodents, graduate student Jun Kim led experiments on the ligand known as CLCF1, which binds the CNTFR receptor. One set of targeted amino acid substitutions converted CLCF1 into a superagonist. When applied to cultured injured neuronal cells, this engineered ligand strengthened the signaling pathways that promote axon extension, indicating it encouraged damaged neurons to regenerate their axons and potentially recover function.
In contrast, by introducing a different combination of amino acid changes to CLCF1, the team converted the same ligand into a potent antagonist. This antagonist variant blocked CNTFR signaling in ways that reduced lung tumor growth in mouse models, pointing to a distinct therapeutic application for the engineered molecule.
Translational potential and ongoing work
Cochran has long pursued engineered proteins as candidates for cancer therapies and regenerative medicine. Several molecules developed in her lab have advanced through preclinical testing, and one of her most advanced therapeutics—designed for ovarian and kidney cancer—has progressed into human clinical trials. Those successes reinforce the promise of engineered ligands and receptors as a versatile drug class for treating diverse conditions including neurodegenerative disease, cancer, osteoporosis and atherosclerosis.
“I have long been fascinated with how proteins function as nature’s molecular machines, and how the tools of engineering allow us to shape protein structure and function with the creativity of an artist, using amino acids as our palette,” Cochran said.
Team and collaborators
Jennifer Cochran is the Shriram Chair of the Department of Bioengineering at Stanford University, a Professor of Bioengineering and, by courtesy, Chemical Engineering, and a member of several interdisciplinary institutes at Stanford including Stanford ChEM-H, Bio-X, the Cardiovascular Institute, the Maternal & Child Health Research Institute (MCHRI), and the Wu Tsai Neurosciences Institute. Stanford co-authors include Assistant Professor of Bioengineering Possu Huang, MD PhD student Cesar Marquez, and graduate student R. Andres Parra Sperberg. Additional contributors to the study came from Soongsil University in South Korea and Tencent AI Lab in China.
Funding
This research received support from graduate fellowships through the Stanford Bio-X Program, the Howard Hughes Medical Institute, the Stanford Medical Scientist Training Program, and the National Institute of Standards and Technology (NIST). Research funding also came from the Lungevity Foundation, Upstage Lung Cancer, the American Lung Association, a Stanford Coulter Foundation Translational Partnership Award, the National Cancer Institute, the U.S. Department of Energy Office of Science through the SciDAC program, the National Research Foundation of Korea, and computing resources from Tencent AI Lab.
Publication
The study will appear in Proceedings of the National Academy of Sciences (PNAS).
Media contact
Tom Abate – Stanford
Image credit
The image in this article is in the public domain.