Interrogating Ras-ERK Interactions and Roles in Tumor Cell Biology

Chuan-Hsiang Huang, MD, PhD

Chuan-Hsiang (“Bear”) Huang, MD, PhD, is an assistant professor of pathology at Johns Hopkins University School of Medicine in Baltimore. Cancer Network asked Dr. Huang about his lab’s research on Ras-ERK protein interactions within cancer cells, funded by the National Institutes of Health and US Defense Advanced Research Projects Agency.

-Interviewed by Bryant Furlow

Cancer Network:How do the Ras enzymes affect ERK protein production, and what role does the Ras-ERK pathway play in normal, nonmalignant cells?

Dr. Huang: Ras proteins, when activated by growth factors and other signals, change their conformation, allowing them to bind other proteins and trigger a cascade of events that culminates in the activation of ERK. In normal cells, the Ras-ERK pathway regulates many cellular processes, including cell proliferation, differentiation, and migration.

Cancer Network:Why has targeting Ras as a cancer treatment been such a challenge?

Dr. Huang: Directly targeting Ras proteins has proven challenging mainly due to their structural features. Inhibitors for other proteins in the pathway, including BRAF, MEK, and the upstream EGFR, are used clinically to treat several types of cancers, such as lung cancer and melanoma. However, many cases eventually develop resistance after initially responding to these inhibitors.

Cancer Network: Your lab recently reported on Ras and ERK protein distributions and interactions in different types of cancer cells, tracked using fluorescent molecular tags. What led you to investigate the distribution of Ras and ERK pulses in cells? 

Dr. Huang: Our study was inspired by the recent reports of pulsatile activation of ERK in single cells, made possible by advances in microscopy. Our previous research on migrating cells demonstrated that Ras activation occurs at localized patches in cells due to the so-called “excitable” property of the signaling network. We therefore sought to determine the correlation between the localized patches of Ras and the global pulses of ERK, as well as the functional and mechanistic relationship between them. 

Cancer Network:You found that Ras activation occurred in a patchy manner at protrusions in cell membranes-and that this triggered cell-wide pulses of ERK. Does that imply that the Ras-ERK pathway is involved in cells’ interaction with the tumor microenvironment?

Dr. Huang: That is correct. We think that patches of Ras activation on protrusions allow both normal and tumor cells to probe their local environments. Different environmental stimuli, which may be chemical or mechanical in nature, are integrated by the molecular network involved in generating protrusions, and the output triggers ERK pulses, which then regulate cell growth. Therefore, cells can use protrusions to sense the environment and “decide” when to divide.

Cancer Network:Does that insight have implications for tumor growth, infiltration of adjacent tissues, or metastasis? 

Dr. Huang: Our findings reveal a deeper link between the apparently distinct processes of cell movement and growth: metastasis and invasion depend on the motility of cancer cells, but the protrusions in these motile cells can send a signal to the machinery that controls cell growth. Therefore, an intriguing thought is that cancer cells metastasize because they want to continue growing. 

Cancer Network:What are the potential clinical implications longer term?

Dr. Huang: Our findings demonstrated that the activity of Ras-ERK signaling is modulated through changing the frequency of the pulses and protrusions, which result from the interaction between a network of proteins. A better understanding of the network structure and dynamics will allow us to control its frequency of “firing” and has important implications for the treatment of cancer.

Cancer Network:What’s next?

Dr. Huang: We have a partial “parts list” of the network that drives Ras-ERK pulses, and how different components are linked to each other. But there are gaps that need to be filled. Our current effort aims to elucidate the complete structure of the network and its spatiotemporal dynamics in cells. Ultimately the knowledge will allow us to design a rational approach for treating the many types of cancers with mutations in this pathway.