Heterogeneity of liver cancer cells helps explain tumor progression in patients

January 15, 2020

(New York, NY - January 15, 2020) - Many liver cancer tumors contain a highly diverse set of cells, a phenomenon known as intra-tumor heterogeneity that can significantly affect the rate at which the cancer grows, Mount Sinai researchers report. The immune system's contribution to this heterogeneity can have major clinical implications.

In a study published in January in Nature Communications, the team reported that this heterogeneity--either within the same tumor or between different tumor regions in the same tumor nodule--appears in about 30 percent of patients with hepatocellular cancer (HCC), the most common form of liver cancer, and that some of these tumors grow rapidly by hijacking different gene networks.

"Tumors are a complex ecosystem, and we're developing for the first time a blueprint of the different ways they can evolve in patients with liver cancer by interacting with the immune system," says Augusto Villanueva, MD, PhD, Assistant Professor in the Liver Cancer Program at The Tisch Cancer Institute at Mount Sinai, and corresponding author of the study. "By better understanding how tumors progress, we're learning more about how they adapt to pharmacological pressures, and how they can develop mechanisms of resistance to cancer therapies. This greater awareness will hopefully lead to the identification of biomarkers that can predict which patients will be responsive to treatment."

Among the clinical implications associated with intra-tumor heterogeneity identified by the research team was the discovery that a single liver cancer biopsy could potentially mischaracterize a liver tumor.

"Some tumors are very homogeneous in terms of their genetic makeup and immune cell infiltration, while others are very heterogeneous," says Dr. Villanueva. "This means that a biopsy from the same tumor could yield different information depending on where it was taken, and could thus affect clinical decision-making for the patient. That's why our work aimed at learning how tumors evolve and the different trajectories they can take is so important to future cancer research, as well as to effectively treating the disease."

As immunotherapy continues to transform cancer research and treatment, one of the most promising areas is liver cancer, which has become the fastest-rising malignancy in the United States in terms of incidence and mortality, responsible for 33,000 new cases annually. Two phase 2 clinical trials using PD-1 immune checkpoint inhibitors, which help the body's immune system recognize and attack cancerous cells, have achieved unprecedented responses in humans, prompting the Food and Drug Administration to grant them accelerated approval status for second-line treatment of advanced hepatocellular cancer.

More recently, a phase 3 clinical trial combining a PD-1 immune checkpoint inhibitor with an antiangiogenic improved survival compared to the current first-line standard of care, sorafenib. Still, only about 30 percent of patients with HCC are believed to respond favorably to immune checkpoint inhibition--an outcome not uncommon with immunotherapies.

"The immune system imposes significant constraints on liver cancer evolution, and by investigating the interaction of immune cells and cancer cells at the molecular level we're trying to predict or anticipate mechanisms of tumor resistance," explains Bojan Losic, PhD, Associate Professor of Genetics and Genomic Sciences, Cancer Immunology Program, at Icahn School of Medicine at Mount Sinai, and lead author of the study. "Our work is particularly relevant considering the remarkable success of immune checkpoint inhibitors in some heterogeneous solid tumors."

To understand the mechanisms that drive tumor progression on a patient-by-patient basis, the research team from Mount Sinai and other medical centers around the world performed an integrated molecular analysis of gene expression, immune activities, and DNA mutations from multiple regions of the same tumor nodule in 14 liver cancer patients. The study was the first to use single-cell RNA sequencing in multiple regions of the same tumor nodule, and was among the first to assess the contribution of the immune system to liver cancer evolution.
-end-
The Mount Sinai-led study consisted of researchers from the University of Sao Paulo School of Medicine in Brazil; the University Medical Center Hamburg-Eppendorf in Hamburg, Germany; Lausanne University Hospital CHUV in Switzerland; Universitat de Barcelona in Spain; Clinica Universidad de Navarra in Spain; Dalhousie University in Halifax, Nova Scotia; and IBM Research.

About the Mount Sinai Health System

The Mount Sinai Health System is New York City's largest integrated delivery system, encompassing eight hospitals, a leading medical school, and a vast network of ambulatory practices throughout the greater New York region. Mount Sinai's vision is to produce the safest care, the highest quality, the highest satisfaction, the best access and the best value of any health system in the nation. The Health System includes approximately 7,480 primary and specialty care physicians; 11 joint-venture ambulatory surgery centers; more than 410 ambulatory practices throughout the five boroughs of New York City, Westchester, Long Island, and Florida; and 31 affiliated community health centers. The Icahn School of Medicine is one of three medical schools that have earned distinction by multiple indicators: ranked in the top 20 by U.S. News & World Report's "Best Medical Schools", aligned with a U.S. News & World Report's "Honor Roll" Hospital, No. 12 in the nation for National Institutes of Health funding, and among the top 10 most innovative research institutions as ranked by the journal Nature in its Nature Innovation Index. This reflects a special level of excellence in education, clinical practice, and research. The Mount Sinai Hospital is ranked No. 14 on U.S. News & World Report's "Honor Roll" of top U.S. hospitals; it is one of the nation's top 20 hospitals in Cardiology/Heart Surgery, Diabetes/Endocrinology, Gastroenterology/GI Surgery, Geriatrics, Gynecology, Nephrology, Neurology/Neurosurgery, and Orthopedics in the 2019-2020 "Best Hospitals" issue. Mount Sinai's Kravis Children's Hospital also is ranked nationally in five out of ten pediatric specialties by U.S. News & World Report. The New York Eye and Ear Infirmary of Mount Sinai is ranked 12th nationally for Ophthalmology, Mount Sinai St. Luke's and Mount Sinai West are ranked 23rd nationally for Nephrology and 25th for Diabetes/Endocrinology, and Mount Sinai South Nassau is ranked 35th nationally for Urology. Mount Sinai Beth Israel, Mount Sinai St. Luke's, Mount Sinai West, and Mount Sinai South Nassau are ranked regionally.

For more information, visit https://www.mountsinai.org or find Mount Sinai on Facebook, Twitter and YouTube.

The Mount Sinai Hospital / Mount Sinai School of Medicine

Related Immune System Articles from Brightsurf:

How the immune system remembers viruses
For a person to acquire immunity to a disease, T cells must develop into memory cells after contact with the pathogen.

How does the immune system develop in the first days of life?
Researchers highlight the anti-inflammatory response taking place after birth and designed to shield the newborn from infection.

Memory training for the immune system
The immune system will memorize the pathogen after an infection and can therefore react promptly after reinfection with the same pathogen.

Immune system may have another job -- combatting depression
An inflammatory autoimmune response within the central nervous system similar to one linked to neurodegenerative diseases such as multiple sclerosis (MS) has also been found in the spinal fluid of healthy people, according to a new Yale-led study comparing immune system cells in the spinal fluid of MS patients and healthy subjects.

COVID-19: Immune system derails
Contrary to what has been generally assumed so far, a severe course of COVID-19 does not solely result in a strong immune reaction - rather, the immune response is caught in a continuous loop of activation and inhibition.

Immune cell steroids help tumours suppress the immune system, offering new drug targets
Tumours found to evade the immune system by telling immune cells to produce immunosuppressive steroids.

Immune system -- Knocked off balance
Instead of protecting us, the immune system can sometimes go awry, as in the case of autoimmune diseases and allergies.

Too much salt weakens the immune system
A high-salt diet is not only bad for one's blood pressure, but also for the immune system.

Parkinson's and the immune system
Mutations in the Parkin gene are a common cause of hereditary forms of Parkinson's disease.

How an immune system regulator shifts the balance of immune cells
Researchers have provided new insight on the role of cyclic AMP (cAMP) in regulating the immune response.

Read More: Immune System News and Immune System Current Events
Brightsurf.com is a participant in the Amazon Services LLC Associates Program, an affiliate advertising program designed to provide a means for sites to earn advertising fees by advertising and linking to Amazon.com.