How a Better Understanding of Metastasis May Lead to Better Cancer Treatment

Sometimes doctors say that people don’t die from cancer, they die from metastasis — that is, from the spread of cancer from an initial “primary” tumor to other parts of the body.

“We know how to control primary tumors — with surgery, chemotherapy, and radiation,” says physician-scientist Karuna Ganesh, MD, PhD, whose lab at Memorial Sloan Kettering Cancer Center (MSK) is dedicated to understanding metastatic disease. “But the cancer cells that manage to survive treatment become more and more aggressive, until eventually we can’t stop them.”

That’s why Dr. Ganesh and other researchers across MSK are working to illuminate the mysteries of metas­tasis and to identify opportunities to slow or even stop its relentless march.

Some of their recent discoveries are providing crucial insights into metastatic cancer and pointing toward new opportunities for potential treatments.

And there’s reason for hope. Already, a growing number of people are living longer with metastatic cancer thanks to advances in treatments and supportive care, the National Cancer Institute reports. Deaths from breast cancer alone dropped 58% between 1975 and 2019 — with nearly a third of the drop due to advances in treating meta­static breast cancer — a recent multicenter study found.

“At MSK, we are attacking the problem from all sides,” says Joan Massagué, PhD, a world-renowned metastasis researcher and Chief Scientific Officer for MSK. “Our ultimate goal is to turn metastatic cancer into a manageable chronic condition and, perhaps one day, to be able to stop it for good.”

Researchers across MSK are approaching a wide variety of metastatic cancer types from many directions.

Analyzing Metastatic Lung Cancer Cells

A team led by thoracic sur­geon David Jones, MD, recently established the first living-organism model of patient-derived organ­oids (mini 3D tissue models made from a patient’s cancer cells) to investigate lung cancer metastasis in individuals. The new model aims to help doctors understand tumor evolution, assess the effec­tiveness of different drugs against a tumor, reveal mechanisms of resistance to targeted therapies, and help personalize strategies for immunotherapy.

“Creating these models directly from our patient’s lung cancer cells adds yet another important tool for us to better understand the biology of lung cancer and to identify ways to better predict its behavior and treat the cancer with specific therapies,” says Dr. Jones, who co-directs MSK’s Fiona and Stanley Druckenmiller Center for Lung Cancer Research.

Advancing Treatment Options for Leptomeningeal Metastasis

Meanwhile, neuro-oncologist Adrienne Boire, MD, PhD, is leading a clinical trial that grew out of MSK research that targets cancer that has spread to the fluid and tissues of the spinal column and brain (leptomeningeal metastasis).

The team showed that cancer cells were able to survive in this challenging environment by repro­gramming themselves to outcom­pete other cells for iron; this fuels their growth while also preventing immune defenders in the area from getting enough iron, which they need to function well.

“Commandeering the iron is an elegant solution on the part of the cancer cell,” Dr. Boire says. “It’s really unique biology that allows them to outcompete the body’s defenders.”

Based on that discovery, doctors at MSK are now determining whether a drug called deferoxamine could be an effective treatment for leptomeningeal metastases by helping to remove iron from the cerebrospinal fluid.

Discovering How Metastatic Cancer Cells Adapt To Survive

Another recent high-profile study by MSK researchers illuminated new and dramatic differences between metastatic cancer cells and cells in the primary tumors they break away from — suggesting opportunities for these differences to be harnessed to fight metastasis.

Metastatic cells have more “plasticity” than their primary tumor counterparts — meaning their cellular identities are more fluid, a collaboration between Dr. Ganesh and computational biologist Dana Pe’er, PhD, found.

When colorectal cancer cells metastasize, they found, they look less and less like the intestinal cells they started out as. In fact, they begin to resemble completely different types of cells — like skin cells or neuroendocrine cells. Essen­tially, they travel back in time to an early development phase, when the cell’s identity wasn’t yet decided. “All this time traveling that cancer cells do is a survival mechanism,” Dr. Ganesh says. “It’s an adaptation to help them survive the assaults of cancer treatment. And we think this time traveling is actually a vulnerability that we could target.”

Dr. Ganesh and her colleagues see two potential opportunities to interrupt metastasis as a result: finding a way to prevent cells from entering this early state, as well as targeting the state itself. Research into both approaches is ongoing at MSK.

The Challenges of Studying Metastasis

There are a number of factors that make metastasis difficult to study — and reasons why MSK is well-positioned to meet those challenges.

One challenge is that metastatic cells may seed themselves in a variety of locations throughout the body, each with a unique microenvironment that can influence the behavior of the cancer cells.

A recent collaboration between Dr. Pe’er and Christine Iacobuzio- Donahue, MD, PhD, who heads the David M. Rubenstein Center for Pancreatic Cancer Research at MSK, examined the differences in genes that are turned on in genetically identical cancer cells — called clones — that had spread to different locations in the body.

“What we see is that these clones are able to adapt to the pressures and metabolic demands of very different environments,” Dr. Pe’er says. “And we see that they’re able to access different gene programs that allow them to thrive in different places, different organs.”

Moreover, even genetically different cancer cells tend to adapt to specific situations by accessing the same gene programs.

“The big question of a cancer cell is, ‘Are you plastic or not?’ And once you are, you can acquire all these different traits. The environment is what really determines what traits will be most advantageous,” she says.

Funding Future Metastatic Cancer Discoveries

One of the critical supports for metastasis research at MSK comes from generous philanthropic gifts.

Dr. Boire was recently selected to be the new Scientific Director of the Alan and Sandra Gerry Metasta­sis and Tumor Ecosystems Center. The center brings together a diverse group of laboratory scientists and clinicians and provides additional resources to support projects focused specifically on metastasis.

“It would be hard to overstate the impact of this center in the progress we’ve made already and will continue to make in the coming years,” Dr. Massagué says.

“The center creates synergies across MSK by improving access to clinical samples for research, devel­oping and sharing new techniques and models, and encouraging new talent to join the endeavor,” Dr. Boire says.

“MSK investigators are leading the way in illuminating the mecha­nisms of metastasis,” she adds.

Additional support for metas­tasis research is also being provided by the Marie-Josée and Henry R. Kravis Cancer Ecosystems Project. Its goal is to fund ambitious laboratory research aimed at moving beyond the study of genetic mutations that drive cancer to understand how malig­nant cells get empowered or de­feated by the greater ecosystem of the body and individual types of tissue. Funding these early-stage studies is critical for securing more substantial grants from the National Institutes of Health and elsewhere.

“MSK is uniquely positioned to make significant progress against metastasis in the coming years — thanks to this visionary philanthropic support, combined with our scien­tific talent, and the robust partner­ships between our clinical and laboratory research communities,” says Dr. Massagué, who oversees the Ecosystems Project.