Newswise — Nutley, NJ, November 17, 2021 – The secret to melanoma’s metastatic spread could be a complex natural pathway it hijacks - one which may be a therapeutic target in combination with other targeted therapies and immunotherapies, according to new research published by Hackensack Meridian Center for Discovery and Innovation (CDI) scientists.
The laboratory of Byungwoo Ryu, Ph.D., and colleagues at the CDI demonstrated the pathway centered around a bone morphogenetic protein known as BMP6 might be the main way melanoma seeks to take over the body, according to the publication in the journal Molecular Cancer Research.
“Metastasis is the main reason cancer patients die,” said Ryu, an associate member of the CDI, and also a research member of the Georgetown Lombardi Comprehensive Cancer Center, of which Hackensack University Medical Center’s John Theurer Cancer Center is part. “If we can prevent cell motility, we can prevent cancer from spreading - and save lives. That is what we are aiming to do through our science.”
“This is good work by the Ryu laboratory, and the findings are therapeutically relevant for melanoma, in terms of preventing metastases in the future,” said Benjamin Tycko, M.D., Ph.D., member of the CDI and also an author of the paper. “This is the kind of translational work that could be a veritable boon for patients in the near future.”
Melanoma starts as a localized lesion - but once it reaches the point of metastasis, it becomes a killer: just 27 percent of the patients who reached stage 4 of the disease survive, even with the latest immunotherapies, according to the American Cancer Society.
Cancers are all known to take over natural processes of the body in order to promote their spread. Ryu and colleagues identify perhaps the main culprit in the spread of melanoma: the silencing of a protein known as BMP6 (bone morphogenetic protein 6).
In a complex chain reaction, the BMP6 is silenced by an epigenetic “eraser complex” known as SIN3A-HDAC1/2 fostered by the cancer. The lack of BMP6 expression then cascades into abnormal silencing of an intracellular signaling pathway mediated by a protein called SMAD5 (Small Mothers Against Decapentaplegics 5). The ultimate effect downstream is the aberrant over-production of yet another protein, FAM83G/PAWS1.
This final step is exactly what the cancer seeks to spread beyond the initial lesion: since the FAM83G/PAWS1 promotes cancer cell motility and cell migration, it allows the cancer cells to spread more quickly through the body, as Ryu and team demonstrated in an animal model of melanoma metastasis using clinical skin cancer samples.
The molecular “chain reaction” connections were shown through the use of a noble small molecule compound called Corin, developed in the lab of Philip Cole, M.D., another one of the authors on the paper, from Brigham and Women’s Hospital and Harvard Medical School. The Corin was synthesized in Cole’s laboratory to inhibit HDAC1/2 and KDM1A - meaning it cuts off the cascade right at the beginning with the “eraser complex” at the start, before BMP6 is impacted.
“We showed that, using the Corin, the cancer was not actively spreading and proliferating in the model,” said Ryu. “We believe the compound could be a therapeutic agent that could be extremely effective in combination with other clinically approved melanoma drugs. It could make a big difference for keeping the cancer cells from spreading and recurrence.”
The Ryu laboratory is conducting follow-up work using cutting edge technologies such as transcriptome and proteome analysis and building a better metastasis model. Two questions they hope to answer in the laboratory: how the FAM83G at the end of the epigenetic cascade resulting in metastasis regulates the intrinsic machinery of cell motility that cancer cell hijacks for spreading - and whether this FAM83G itself is a viable target for preventing melanoma from spreading, perhaps via adjuvant drugs in combination with other molecularly targeted therapies.
Additionally, the team is investigating other epigenetic “eraser complexes” such as CoREST and NuRD complexes which may be involved in metastatic cancer development and therapy resistance.
“This is the kind of bench science which promises great bedside benefits in the future,” said Ihor Sawczuk, M.D., FACS, the chief research officer and president of the Northern Region for Hackensack Meridian Health. “The CDI’s work is an investment into the health of our years to come.”
ABOUT HACKENSACK MERIDIAN HEALTH
Hackensack Meridian Health is a leading not-for-profit health care organization that is the largest, most comprehensive and truly integrated health care network in New Jersey, offering a complete range of medical services, innovative research and life-enhancing care.
Hackensack Meridian Health comprises 17 hospitals from Bergen to Ocean counties, which includes three academic medical centers – Hackensack University Medical Center in Hackensack, Jersey Shore University Medical Center in Neptune, JFK Medical Center in Edison; two children’s hospitals - Joseph M. Sanzari Children’s Hospital in Hackensack, K. Hovnanian Children’s Hospital in Neptune; nine community hospitals – Bayshore Medical Center in Holmdel, Mountainside Medical Center in Montclair, Ocean Medical Center in Brick, Palisades Medical Center in North Bergen, Pascack Valley Medical Center in Westwood, Raritan Bay Medical Center in Old Bridge, Raritan Bay Medical Center in Perth Amboy, Riverview Medical Center in Red Bank, and Southern Ocean Medical Center in Manahawkin; a behavioral health hospital – Carrier Clinic in Belle Mead; and two rehabilitation hospitals - JFK Johnson Rehabilitation Institute in Edison and Johnson Rehabilitation Institute in Brick.
Additionally, the network has more than 500 patient care locations throughout the state which include ambulatory care centers, surgery centers, home health services, long-term care and assisted living communities, ambulance services, lifesaving air medical transportation, fitness and wellness center, rehabilitation centers, urgent care centers and physician practice locations. Hackensack Meridian Health has more than 36,000 team members, and 7,000 physicians and is a distinguished leader in health care philanthropy, committed to the health and well-being of the communities it serves.
The network’s notable distinctions include having more top-ranked hospitals than anyone in New Jersey, as recognized by U.S. News & World Report. Hackensack University Medical Center is the only hospital in New Jersey with the #1 adult and children’s hospital rankings.
John Theurer Cancer Center at Hackensack University Medical Center is New Jersey's best cancer center, as recognized by U.S. News & World Report. This premier cancer center is also the largest and most comprehensive center dedicated to the diagnosis, treatment, management, research, screenings, and preventive care as well as survivorship of patients with all types of cancers. John Theurer Cancer Center is part of Georgetown Lombardi Comprehensive Cancer Center, an NCI designated comprehensive cancer center.
Additionally, the network partnered with Memorial Sloan Kettering Cancer Center to ensure that patients have access to the highest quality, most individualized cancer care when and where they need it.
The Hackensack Meridian School of Medicine, the first private medical school in New Jersey in more than 50 years, welcomed its first class of students in 2018 to its campus in Nutley and Clifton. The Hackensack Meridian Center for Discovery and Innovation (CDI), housed in a fully renovated state-of-the-art facility, seeks to translate current innovations in science to improve clinical outcomes for patients with cancer, infectious diseases and other life-threatening and disabling conditions.
Hackensack Meridian Health is a member of AllSpire Health Partners, an interstate consortium of leading health systems, to focus on the sharing of best practices in clinical care and achieving efficiencies. To learn more, visit www.hackensackmeridianhealth.org.
ABOUT THE CENTER FOR DISCOVERY AND INNOVATION
The Center for Discovery and Innovation, a member of Hackensack Meridian Health, translates current innovations in science to improve clinical outcomes for patients. More than 18 laboratories, 155 professional researchers and physician-scientists at the CDI have set their sights on cancer, infectious diseases, autoimmune disorders, and other acute and chronic diseases. Clinical need drives the scientific insights, and their application, for these researchers, as shown in the real-time response to the COVID-19 pandemic, resulting in new diagnostics, therapies, and surveillance abilities. The CDI leverages a new wave of scientific advances involving genetics, cell engineering of the human immune system, and imaging to better diagnose, treat and prevent disease through personalized medicine approaches. For additional information, please visit www.hmh-cdi.org.
RSS