Metastasis, the spread of cancer in the body, is responsible for 90% of all deaths from solid tumors, making its prevention the single most important challenge in oncology today. At Memorial Sloan Kettering Cancer Center (MSK) understanding this phenomenon is one of our most pressing goals and recently our scientists have made a series of crucial discoveries. Described below, these findings not only add to our fundamental understanding of what metastasis is but also open the door to promising new treatments.
To metastasize, cancer cells must escape a tumor, travel through the bloodstream, and replicate in healthy tissues. To survive this unlikely journey, MSK investigators have determined that cells must do three things: acquire regenerative behavior, evade the immune system, and adapt in a new environment.
MSK’s research team is shedding light on all three mechanisms with the goal of overcoming them and saving lives. Here we highlight some of our most recent work in metastasis research.
Acquiring Regenerative Behavior
MSK scientists have discovered that metastasis is carried out by a small population of cancer cells that assume the role of a rogue emergency repair crew, regenerating abnormal tissue at a new site in the same way the healthy body recruits special stem cells to heal a wound. Knowing metastatic cells must adopt this regenerative behavior has spawned intensive research into how metastasis begins and how it can be shut down.
• MSK physician-scientist Karuna Ganesh, MD, PhD, an Assistant Member in the Molecular Pharmacology Program at SKI, led a revelatory study with Dr. Massagué that provides a new of understanding how metastatic cells interact with wound-healing pathways. Using an advanced model of colorectal cancer based on organoids (3D organlike tissues derived from patient tumor samples), they found that the protein-coding gene L1CAM is able to co-opt the wound-healing regenerative process and deploy it in metastasis-initiating cells—revealing that metastasis is essentially wound healing gone wrong.
- Cancer cells grow into metastases by influencing the connective tissue and blood vessels in and around the tumor. These changes create a microenvironment like that of a non-healing wound—in both situations, there is abnormal blood vessel growth and a constant flow of immune cells. A Member of the Immunology Program at SKI, Ming Li, PhD, and his team are learning how a tumor impacts its microenvironment and whether the tumor’s cells can be reprogrammed to suppress tumor progression. Most immune cells found in most solid tumors are a type called tumor-associated macrophages (TAMs). Dr. Li traced the TAMs and found that they infiltrate tumors that contain low levels of mTORC1, a protein complex involved with cell metabolism. By blocking certain proteins, researchers in Dr. Li’s lab increased mTORC1 activity in the laboratory, causing tumor cell death and halting cancer progression. The hope is that, with additional research, these insights can be translated to stop metastasis in patients.
- A cellular transformation known as epithelial-mesenchymal transition (EMT) allows tumor cells to spread through the body by escaping in and out of the bloodstream. EMT is also necessary for the formation of normal tissue layers in wound healing, organs, and developing embryos. MSK fellow Jie Su, PhD, and his colleagues posed the question: What triggers EMT? The answer: the TGF-beta pathway, a series of chemical reactions within a cell. When TFG-beta links with another pathway, it triggers EMT during cancerous tissue development—a critical step in metastasis.
Outsmarting the Immune System
The immune system naturally monitors cancer cells as they try to regenerate tissue in the wrong place, a process that should look suspicious and disorderly to immune defenses. Metastatic cells share similarities with certain adult stem cells, however, including a plasticity that allows them to take on different identities. Learning how cancer cells maneuver in the body to establish a new tumor is the goal of the following research.
- Cancer cells ability to assume different identities is one reason they are so difficult to outsmart. As a Massagué Lab fellow, Ashley Laughney, PhD, and her colleagues used models of lung cancer to demonstrate that by subverting certain tissue repair mechanisms used in wound-healing, tumors can ramp up cell diversity. This uptick in heterogeneity leads to better tumor cell adaptation and immune evasion.
- Brain metastases are 10 times more common than tumors that originate there and occur in up to 40% of adults with cancer. Malignancies in the brain are extremely challenging to treat because despite letting in cancer cells the blood-brain barrier often blocks or weakens the effects of therapies. Dr. Massagué and his colleagues made the exciting discovering that when circulating tumor cells reach the brain, they hug capillaries and express proteins that overcome the brain’s defense against metastatic invasion. The protein that helps the cells stick to nutrient-filled blood vessels, L1CAM, has since emerged as a strong target for potential new drugs. Recently, former Massagué Lab Research Associate Ekrem Emrah Er, PhD, and his colleagues made an additional breakthrough discovery: by spreading along blood vessels to distant tissues, cancers cells trigger mechanical sensors key to allowing cells to form metastatic tumors.
- Up to 90% of pancreatic cancer patients present with metastatic disease or eventually develop it. Christine Iacobuzio-Donahue, MD, PhD, Director of the David M. Rubenstein Center for Pancreatic Cancer Research, and her team take a unique approach to understanding the mechanisms of metastasis using genetic sequencing. By studying primary and metastatic tissue samples obtained from patients who never received treatment, they revealed distinct patterns of mutations that drive tumor development in both the primary pancreatic tumors and their metastases.
- Tumors consist of a remarkably complex groups of cancerous and non-cancerous cells whose diversity is influenced by multiple genetic and environmental factors. This heterogeneity promotes tumor progression, enables metastasis, and poses a challenge for effective cancer treatments. Knowing this, Tuomas Tammela, MD, PhD, an Assistant Member in the Cancer Biology and Genetics Program at SKI, set out to uncover the signaling pathways that maintain cell heterogeneity in tumors and to block the signals that cancer cells hijack from normal stem cells. Reducing cell diversity in tumors makes them more sensitive to therapy and less likely to metastasize. This new way to promote anti-tumor response has the potential to become a first-of-its-kind therapies for patients with no other treatment options.
Adapting to a New Environment
Once metastatic cells are installed in a distant organ, they are under selective pressure to adapt to new host tissues in order to regrow. This tumor microenvironment, where cancer cells and the immune system collide, is complex and altered in the metastatic cells’ favor. Some of the remarkable progress in this previously unexplored area of cancer research is listed below.
- Dr. Pe’er, Dr. Massagué, and MSK physician-scientist Adrienne Boire, MD, PhD, used single-cell sequencing to learn which properties of the brain’s microenvironment allow cancer to spread there. They found that metastatic cancer cells gain the ability to produce potent iron-transporting proteins, normally produced by immune cells, in the cerebrospinal fluid. With this ability, the cancer cells monopolize the iron, disabling the immune response that would normally destroy them. Because the iron transporter can be inhibited therapeutically, the collaborators are now designing a clinical trial.
- Scott Lowe, PhD, the Chair of the Cancer Biology & Genetics Program at SKI, teamed up with Dr. Pe’er to explore how different cells’ biological mechanisms affect pancreatic ductal adenocarcinoma (PDAC)—a highly aggressive cancer that metastasizes early and presents a complex tumor microenvironment. They zeroed in on epigenetic changes, which can turn genes on and off without actually changing DNA. This including switching the cells’ identities, making it possible for them to adapt to new environments and enabling the cancer to spread. Better understanding these dynamics holds tremendous promise for patients with PDAC and other types of cancer.
- To see how tumor cells interact with other cells in the microenvironment, physician-scientist Richard White, MD, PhD, and his team developed a transparent strain of zebrafish called “casper.” This transformative technology has revealed how melanoma cells break off from their site of origin, travel to distant areas in the body, and form cancer cells in a different location. Recently, his work led to a surprising discovery: Melanoma tumors flourish near fat tissue by consuming the lipids found there and grow more aggressively compared to tumors without this energy source. These super-fueled cells can then chew through collagen and cross membranes with ease, allowing them to spread
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