Ask someone, “What is cancer?” and they are likely to answer with what they learned in high school biology: out-of-control cell growth. Though this is commonly known, the molecular mechanisms that regulate cellular growth are less understood and remain an interesting topic for scientists. Determining how these mechanisms operate and become dysregulated is essential in shaping our understanding and treatment of cancer.

To initiate growth, cells tap into the nutrient supply inside and outside of the cell, but it’s unclear how they detect if they have enough nutrients for growth. Stanford Cancer Institute member Kacper Rogala, PhD, is the principal investigator on a recent Nature study that sheds light on how cells sense nutrient availability and use that information to activate or inhibit growth. This is the first study to explain this process on a molecular level.

Rogala and his team investigated the GATOR2 protein complex, which receives and integrates signals from a network of proteins that directly sense the cell’s supply of amino acids, a nutrient cells use to build larger molecules, such as proteins. In the absence of nutrients, nutrient-sensing proteins bind to the surface of GATOR2, and unbind when nutrients are present. Freed GATOR2 transmits the nutrient-availability signal to mTORC1, a key protein that triggers cellular growth. Essentially, GATOR2 is tells mTORC1 that there are enough amino acids to start the growth process.

The study found that when these nutrient-sensing proteins do not have an amino acid bound, they will instead bind to GATOR2 and change its structure, inhibiting growth. The investigators identified two distinct molecular mechanisms that alter GATOR2’s structure. The protein Sestrin2, in the absence of the amino acid leucine, will make portions of GATOR2 more rigid and restrict its ability to relay growth signals. The protein CASTOR1, in the absence of the amino acid arginine, attaches to GATOR2’s central region and reshapes its structure to prevent it from signaling mTORC1.

Rogala explains, “When these nutrient-sensing proteins are not bound to amino acids, they see the cell as starving and instead they bind to GATOR2 to modify its shape so that GATOR2 is unable to do its job.” 

When amino acids become available again, they bind to the nutrient-sensing protein attached to GATOR2 and create a series of structural changes in the proteins that cause them to detach. GATOR2 is then free to send a signal to mTORC1 to activate cellular growth.   

The binding and unbinding of molecules changes GATOR2’s shape and surface chemistry, which affects how GATOR2 interacts with other cellular proteins. Rogala explains that it's like the protein is now speaking a different molecular language, attracting new partners while no longer recognizing previous ones. 

He says, “GATOR2 functions like a molecular sensing board. It receives all these signals and then changes its configuration when those molecules bind or unbind. What’s really fascinating is that multiple signals can bind to it simultaneously, which is where the signal integration comes into place.” 

The investigators used a wide range of methods, including biochemical and structural biology techniques and advanced computational analyses, to build a detailed model of how cells sense dietary amino acids and translate this information into cell growth.

Maximilian Wranik, PhD, a Life Science Alliance Bridging Excellence Postdoctoral Fellow at the Stanford Cancer Institute and the study's first author, explains, “We used these methods to really explore the underlying mechanisms of these control processes. By doing that, we observed how GATOR2 attaches different sensor proteins, how these protein complexes form, how they block cellular growth in the absence of nutrients, and how the exposure to nutrients triggers structural changes in GATOR2 and sends an activating message to restart cell growth.” 

Rogala adds, “It’s truly beautiful chemistry at the molecular level. The way these proteins and small molecules talk to one another, how they release inhibition, and basically signal to the cell that they have a good supply of nutrients, allowing the cell to start growing again.”

While this research shows how nutrients bind to sensors and how those sensors interact with GATOR2, how it communicates to mTORC1 is still unknown.

Rogala says, “That’s still a black box for us. We are currently trying to figure out how the signal is passed from GATOR2 to mTORC1 and how this entire growth control process works at the molecular level. The more we learn, the more opportunities we will have for attacking dysregulated cancer growth with pharmacological interventions.”

The necessity of basic science for therapeutic innovation

Most cancers have mTORC1 dysregulation, making it an obvious target for drug development. However, because mTORC1 is essential to all cells’ functioning, past clinical trials of mTORC1 inhibitors had toxic side effects, as the drugs were unable to distinguish between healthy and malignant cells. In contrast, GATOR2 is not an essential gene, so it may be possible to develop drugs that inhibit GATOR2’s activities associated with cell growth without incurring the toxic side effects of mTORC1 inhibitors.

Wranik explains, “Based on these findings, we can now explore creative, innovative ways to interfere with these dysregulated growth processes, translating our fundamental discoveries into innovative ideas to make a meaningful impact for cancer patients.”

Rogala describes his group as idea generators who develop proof-of-concept ideas. He hopes his research will lead to more effective, less toxic, and better-tolerated therapies. 

He explains, “There are many anti-cancer drugs available, and patients often show an incredible initial response. However, over time, cancer cells develop mutations and become resistant, so there’s this constant need for developing new strategies for stopping cancer growth, such that you can deploy them as a so-called cocktail. The cancer cells then have a harder time developing resistance against all of these drugs, and they die.”

Both Rogala and Wranik emphasize the critical role of basic science research in driving therapeutic breakthroughs. 

Wranik says, “This is a great example of how Stanford is approaching science by focusing on a very basic fundamental level but always with this translational aspect in mind. We are trying to understand what comes way before a drug comes to market. Our research lays the foundation for making meaningful contributions in the clinical environment.”

Rogala adds, “This study shows that basic science is so important. There is no applied science without basic science. We are the ones who make the initial discoveries, figure out how things work, and then we take that knowledge and apply it in a clear and targeted way. This ensures that we're not just blindly chasing solutions, but we know exactly what we're going after, and we can get there much faster because we understand the underlying mechanisms and can avoid many potential pitfalls. There is an enormous value in the investment in basic science.”

Karen Linde-Garelli, a Stanford Cancer Biology PhD student, and Yuri Choi, PhD, Stanford Cancer Institute postdoctoral scholar, contributed to the study. This project was a collaboration with researchers at MIT and Harvard.