Mount Sinai Researchers Discover Why Some Colon Cancers Resist Treatment
New study says cancer cells can change into a fetal-like state to evade chemo
About the Visual: Our research shows that in colorectal cancer patients, the diseased intestines (jar) can produce a variety of cancer stem cell states, each with its own unique characteristics. These include well-known LGR5+cells (orange), new and aggressive fetal-like cells (blue), and many in between. This diversity helps colorectal cancer grow and resist treatments, making it harder to fight.
Photo Credit: Gloria Fuentes, Scientific Visual Communicator, The Visual Thinker
Researchers at The Tisch Cancer Institute at Mount Sinai have uncovered a major reason why some colorectal cancers (CRC) resist treatment. Their groundbreaking study, published this week in Nature Genetics, reveals that cancer cells can revert to a fetal-like state, helping them survive and grow despite treatment. This phenomenon, termed “oncofetal reprogramming,” enables some tumor cells to diversify their molecular characteristics and behavior, allowing them to evade chemotherapy.
Colorectal cancer remains one of the deadliest malignancies worldwide, with treatment resistance posing a significant barrier to long-term survival. Prior research has focused on targeting a harmful population of tumor cells known as “LGR5+ cancer stem cells”, but has failed to achieve durable tumor regression. The study suggests this failure is due to some LGR5+ cells transitioning into a fetal-like state, rendering them resistant to current chemotherapies.
“This discovery challenges the conventional belief that colorectal cancer is driven by a single, uniform cancer stem cell population,” said Slim Mzoughi, PhD, Assistant Professor of Oncological Sciences at the Icahn School of Medicine at Mount Sinai and Principal Investigator of the study. “Instead, we demonstrate that multiple distinct cancer stem cell states coexist and cooperate, significantly influencing tumor progression and therapy resistance.”
A New Understanding
Mount Sinai’s research team, in collaboration with several other leading institutions worldwide, found that oncofetal reprogramming helps colon cancer survive by making its cells more adaptable. They also discovered ways to block this process, which could make current cancer treatments work better.
“Our data suggest that inhibiting the oncofetal program in combination with current treatments may provide a powerful approach to overcoming therapy resistance,” said co-investigator Ernesto Guccione, PhD, Professor of Oncological Sciences at Mount Sinai. “This study lays the groundwork for the development of novel targeted therapies that could benefit CRC patients worldwide.”
For clinicians, these findings may offer a deeper understanding of why certain CRC patients experience treatment resistance and disease recurrence. Future therapeutic strategies integrating inhibitors of the oncofetal program with existing chemotherapy regimens could dramatically improve patient outcomes and extend survival.
The research team is now focusing on developing new drugs or repurposing ones already approved by the Food and Drug Administration to target the oncofetal program effectively.
Collaborating institutions include the Institute of Molecular and Cell Biology (A*STAR, Singapore), Max-Delbrück-Center for Molecular Medicine (Germany), Cancer Research UK Scotland Institute, KU Leuven (Belgium), and several others. Study supported by funding from the National Cancer Institute, National Institutes of Health, under the grant titled Functional and Molecular Characterization of Oncofetal Stem Cells in CRC (R01CA292376-01), with a total grant amount of $2.8 million.
About the Icahn School of Medicine at Mount Sinai
The Icahn School of Medicine at Mount Sinai is internationally renowned for its outstanding research, educational, and clinical care programs. It is the sole academic partner for the eight- member hospitals* of the Mount Sinai Health System, one of the largest academic health systems in the United States, providing care to New York City’s large and diverse patient population.
The Icahn School of Medicine at Mount Sinai offers highly competitive MD, PhD, MD-PhD, and master’s degree programs, with enrollment of more than 1,200 students. It has the largest graduate medical education program in the country, with more than 2,600 clinical residents and fellows training throughout the Health System. Its Graduate School of Biomedical Sciences offers 13 degree-granting programs, conducts innovative basic and translational research, and trains more than 500 postdoctoral research fellows.
Ranked 11th nationwide in National Institutes of Health (NIH) funding, the Icahn School of Medicine at Mount Sinai is among the 99th percentile in research dollars per investigator according to the Association of American Medical Colleges. More than 4,500 scientists, educators, and clinicians work within and across dozens of academic departments and multidisciplinary institutes with an emphasis on translational research and therapeutics. Through Mount Sinai Innovation Partners (MSIP), the Health System facilitates the real-world application and commercialization of medical breakthroughs made at Mount Sinai.
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* Mount Sinai Health System member hospitals: The Mount Sinai Hospital; Mount Sinai Beth Israel; Mount Sinai Brooklyn; Mount Sinai Morningside; Mount Sinai Queens; Mount Sinai South Nassau; Mount Sinai West; and New York Eye and Ear Infirmary of Mount Sinai.
About the Mount Sinai Health System
Mount Sinai Health System is one of the largest academic medical systems in the New York metro area, with 48,000 employees working across eight hospitals, more than 400 outpatient practices, more than 600 research and clinical labs, a school of nursing, and a leading school of medicine and graduate education. Mount Sinai advances health for all people, everywhere, by taking on the most complex health care challenges of our time—discovering and applying new scientific learning and knowledge; developing safer, more effective treatments; educating the next generation of medical leaders and innovators; and supporting local communities by delivering high-quality care to all who need it.
Through the integration of its hospitals, labs, and schools, Mount Sinai offers comprehensive health care solutions from birth through geriatrics, leveraging innovative approaches such as artificial intelligence and informatics while keeping patients’ medical and emotional needs at the center of all treatment. The Health System includes approximately 9,000 primary and specialty care physicians and 11 free-standing joint-venture centers throughout the five boroughs of New York City, Westchester, Long Island, and Florida. Hospitals within the System are consistently ranked by Newsweek’s® “The World’s Best Smart Hospitals, Best in State Hospitals, World Best Hospitals and Best Specialty Hospitals” and by U.S. News & World Report's® “Best Hospitals” and “Best Children’s Hospitals.” The Mount Sinai Hospital is on the U.S. News & World Report® “Best Hospitals” Honor Roll for 2024-2025.
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