University of California San Francisco
Helen Diller Family Comprehensive Cancer Center

Mutations, Drugs Drive Cancer by Blurring Growth Signals

Novel Technique Lets Researchers Control Common Cancer Pathway in the Lab with Pulses of Light

By Nicholas Weiler | | September 6, 2018

Mutations, Drugs Drive Cancer by Blurring Growth Signals

The OptoPlate device, developed at UCSF, allows researchers to expose groups of cells engineered to respond to certain wavelengths of light to precisely programmed patterns of input. Photo by Wendell Lim Laboratory

Genetic mutations in a form of non–small cell lung cancer (NSCLC) may drive tumor formation by blurring cells’ perception of key growth signals, according to a new laboratory study published Aug. 31, 2018, in Science.

The research, led by UC San Francisco researchers, could have important implications for understanding and ultimately targeting the defective mechanisms underlying many human cancers.

Healthy cells rely on the central Ras/Erk growth signaling pathway (also known as the Ras/MAPK pathway) to interpret external cues about how and when to grow, divide, and migrate, but defects in how these messages are communicated can cause cells to grow out of control and aggressively invade other parts of the body. Such mutations in are found in the majority of human cancers, making treatments for Ras/Erk defects a “holy grail” of cancer research.

Decades of study have led scientists to believe that Ras/Erk–driven cancers occur when mutations cause one or more components of the pathway to get stuck in a pro-growth state. Researchers have labored to develop targeted treatments that flip these broken switches back off, but so far most have failed to make it through clinical trials. Now, using a high-throughput technique developed at UCSF that allows scientists to take control of Ras/Erk signaling using pulses of light, and then quickly read out resulting genomic activity, researchers have made a surprising discovery about this extensively studied pathway.

Using Optogenetics to Explore Communication Within Individual Cells

Optogenetics – in which light-sensitive proteins are genetically engineered into cells in order to make them respond to pulses of light – has been a transformative laboratory technique in neuroscience, allowing researchers to control and study electrical activity patterns within networks of neurons with exquisite precision.

By using the same approach to explore patterns of chemical communication within individual cells, the new research has revealed that some Ras/Erk mutations may trigger cancer by altering the timing, rather than the intensity, of cellular growth signals. The new study also shows that this blurring of signal timing may explain why some targeted drugs designed to shut off defective Ras/Erk signaling can paradoxically activate the pathway instead potentially raising the risk of new tumor formation.

“This new technique is like a diagnostic instrument that we hook up to a diseased cell, which lets us stimulate and interrogate the cell with many light-based stimuli to see how it responds,” said UCSF synthetic biologist Wendell Lim, PhD, one of the study’s senior authors. “Using this approach, we were able to identify cancer cells that have certain defects in how they process signals, behaviors that lead to cell proliferation in response to signals that normally are filtered by the cell circuits.”

UCSF medical oncologist and cancer biologist Trever Bivona, MD, PhD, and Princeton molecular biologist Jared Toettcher, PhD, formerly a postdoctoral researcher in Lim’s lab, were co–senior authors of the new study. The study’s lead author was Lukasz Bugaj, PhD, of the University of Pennsylvania, also formerly a postdoctoral researcher in Lim’s lab.