Cancer cells team up to survive, spread and grow. A new investigative team led by Fred Hutch Cancer Center breast cancer researcher Kevin Cheung, MD is coming together to unravel how. Supported by a $1 million grant from the Robert J. Kleberg, Jr. and Helen C. Kleberg Foundation, the researchers will explore how clusters of cancer cells communicate to collaborate, and how to target tumor teamwork to help stave off drug resistance and reduce tumor spread.
“When cancer cells cooperate with each other, it allows them to grow more efficiently and metastasize more efficiently,” Cheung said. “We're applying this concept to understanding drug resistance and understanding how these signaling networks might be different between same or different tumor types.”
He has teamed up with Fred Hutch colleagues Nancy Davidson, MD, and Peter Nelson, MD. Davidson, a breast cancer expert, holds the Raisbeck Endowed Chair for Collaborative Research, and Nelson, who studies prostate cancer, holds the Stuart and Molly Sloan Precision Oncology Institute Endowed Chair.
The group’s ultimate goal is to develop new and better cancer drugs aimed at the deadly problems of metastasis and drug resistance. Because cooperation gives cancer-cell clusters so many advantages, Cheung believes that targeting their cooperative strategies could make it harder for them to survive, spread and resist drugs — and easier for us to treat.
When individual organisms — from bacteria to birds — form groups, they can cooperate to perform collective yet decentralized behaviors. Our bodies take advantage of this phenomenon during development as our cells multiply, turn into different cell types and collaborate to build structured tissues that perform specialized functions that keep our whole bodies alive.
Work by Cheung and others has shown that tumors and cancer-cell clusters can exhibit — and take advantage of — these collective, cooperative behaviors. Yet cancer-cell cooperation is about much more than just strength in numbers, Cheung said. It enhances tumor migration and survival, but there’s even more to it.
“Cooperation allows for cancer cells to be more robust,” he said. “When you have a multicellular, organized structure, you can lose any individual cell but the information encoded in the system, and the behavior of the system, can continue to persist. So those type of systems are more resistant to failure. They’re more able to adapt.”
That’s great news for cancer cells facing chemotherapy, but bad news for us. Cheung and his collaborators aim to develop ways to interfere with cancer cells’ cooperation, which could point the way toward new therapies or help current therapies work more effectively.
He has already identified one molecular “bridge” between tumor cells. Called epigen, it’s released into the minuscule spaces between tumor cells and facilitates metastasis. Cheung is sure there are other molecules that allow cancer cells to sense each other and act as a group.
In their hunt for other molecules that enable cancer cooperation, he and his team will start with triple-negative breast cancer. These are breast tumors that don’t produce the estrogen receptor, progesterone receptor or HER2 (human epidermal growth factor 2) — and therefore can’t be treated using therapies that target these molecules.
Patients with triple-negative breast cancer (about 10% of breast cancer patients) face poorer prognoses and worse outcomes. While the five-year survival rate for breast cancer overall is over 90%, it drops to 77% for patients with triple-negative breast cancer. Triple-negative breast tumors are also more likely to metastasize, or spread. The five-year survival rate for patients with metastatic triple-negative disease is just 12.8%.
But triple-negative breast tumors aren’t monolithic. Scientists have identified different molecular patterns that define several subtypes. Cheung suspects that these different flavors of triple-negative breast cancer may also employ different cooperative strategies. Cancer cells may also use different strategies when growing in different tissues.
“We’re going to look at the proteins that are expressed by cooperating cancer cells — uniquely and in these different contexts — and then target them to see if that makes them more sensitive to therapy,” Cheung said. “The challenge is that these intercellular compartments are very small, and the amounts of proteins that exist are minuscule. So we really needed to think of a different, creative approach for getting at this challenge.”
He and his team turned to a Nobel Prize-winning approach: bio-orthogonal click chemistry. This allows scientists to do chemistry in living cells, tagging proteins without disrupting their normal function. Click chemistry can be conducted in breast tumor organoids, which are breast cancer cells growing in 3D clusters that better mimic a tumor’s natural environment than a 2D Petri dish. This will allow Cheung and his team to fish out minute amounts of key proteins, instead of hunting through masses of unimportant molecules for the few critical to cancer collaboration.
With Davidson and Nelson, Cheung hopes to uncover the molecules that different triple-negative subtypes use to cooperate, as well as how a tumor’s environment shapes its cooperatives strategies. To do so, the investigators will integrate the data from Cheung’s click chemistry experiments with molecular and clinical information from breast tumor tissue donated from patients around the world. Nelson's and Davidson’s experience as clinician-scientists is critical to the project, which could not be achieved without funding from the Kleberg Foundation, Cheung said.
“The Kleberg Foundation funding will really allow us to push the frontier and survey these tumor types in a deep way we would not be able to do otherwise,” Cheung said. “Our major goal is to develop therapies that will treat and prevent metastatic breast cancer. This will bring us one step closer to that vision.”
Sabrina Richards, a staff writer at Fred Hutchinson Cancer Center, has written about scientific research and the environment for The Scientist and OnEarth Magazine. She has a PhD in immunology from the University of Washington, an MA in journalism and an advanced certificate from the Science, Health and Environmental Reporting Program at New York University. Reach her at srichar2@fredhutch.org.
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