A study from Weill Cornell Medicine has shed light on a survival mechanism employed by cancers, which often emit molecules into the bloodstream that cause detrimental changes to the liver. These modifications shift the liver into a state of inflammation, leading to a buildup of fat and hindering its regular detoxifying abilities. The research reveals potential avenues for developing new diagnostic tests and treatments to detect and reverse this process.
The study, which was recently published in the journal Nature, discovered that various types of tumors located outside the liver can remotely induce alterations to the liver that mimic fatty liver disease. This transformation is brought about by the secretion of extracellular vesicles and particles (EVPs) loaded with fatty acids. Evidence of this mechanism was discovered in both animal cancer models and the livers of human cancer patients.
“Our findings show that tumors can lead to significant systemic complications including liver disease, but also suggest that these complications can be addressed with future treatments,” said study co-senior author Dr. David Lyden, the Stavros S. Niarchos Professor in Pediatric Cardiology and a professor of pediatrics and of cell and developmental biology at Weill Cornell Medicine.
Tumor cell-derived EVPs induced accumulation of lipid droplets in the mouse liver. Green, lipid droplet. Blue, DAPI. Credit: Gang Wang, Jianlong Li, David Lyden
For the past two decades, Dr. Lyden, who is also a member of the Gale and Ira Drukier Institute for Children’s Health and the Sandra and Edward Meyer Cancer Center at Weill Cornell Medicine, and his research group have been studying the systemic effects of cancers. These effects reflect specific strategies cancers use to secure their survival and speed their progression. In their work published in 2015, for example, the team discovered that pancreatic cancers secrete molecules encapsulated in extracellular vesicles, that travel through the bloodstream, are taken up by the liver, and prepare the organ to support the outgrowth of new, metastatic tumors.
In the new study, the researchers uncovered a different set of liver changes caused by distant cancer cells which they observed in animal models of bone, skin, and breast cancer that metastasize to other organs but not to the liver. The study’s key finding is that these tumors induce the accumulation of fat molecules in liver cells, consequently reprogramming the liver in a way that resembles the obesity- and alcohol-related condition known as fatty liver disease.
The team also observed that reprogrammed livers have high levels of inflammation, marked by elevated levels of tumor necrosis factor-α (TNF-α), and low levels of drug-metabolizing enzymes called cytochrome P450, which break down potentially toxic molecules, including many drug molecules. The observed reduction in cytochrome P450 levels could explain why cancer patients often become less tolerant of chemotherapy and other drugs as their illness progresses.
The researchers traced this liver reprogramming to EVPs that are released by the distant tumors and carry fatty acids, especially palmitic acid. When taken up by liver-resident immune cells called Kupffer cells, the fatty acid cargo triggers the production of TNF-α, which consequently drives fatty liver formation.
Although the researchers principally used animal models of cancers in the study, they observed similar changes in the livers of newly diagnosed pancreatic cancer patients who later developed non-liver metastases.
“One of our more striking observations was that this EVP-induced fatty liver condition did not co-occur with liver metastases, suggesting that causing fatty liver and preparing the liver for metastasis are distinct strategies that cancers use to manipulate liver function,” said co-first author Dr. Gang Wang, a postdoctoral associate in the Lyden laboratory. Dr. Jianlong Li, a scientific collaborator in the Lyden laboratory, is also a co-first author of the study.
The scientists suspect that the fatty liver condition benefits cancers in part by turning the liver into a lipid-based source of energy to fuel cancer growth.
“We see in liver cells not only an abnormal accumulation of fat but also a shift away from the normal processing of lipids so that the lipids that are being produced are more advantageous to the cancer,” said co-senior author Dr. Robert Schwartz, associate professor of medicine in the Division of Gastroenterology and Hepatology and a member of the Meyer Cancer Center at Weill Cornell Medicine and a hepatologist at NewYork-Presbyterian/Weill Cornell Medical Center.
That may not be the only benefit that cancers derive from this liver alteration. “There are also crucial molecules involved in immune cell function, but their production is altered in these fatty livers, hinting that this condition may also weaken anti-tumor immunity,” said co-senior author Dr. Haiying Zhang, assistant professor of cell and developmental biology in pediatrics at Weill Cornell Medicine.
The researchers were able to mitigate these systemic effects of tumors on the livers by implementing strategies such as blocking tumor-EVP release, inhibiting the packaging of palmitic acid into tumor EVPs, suppressing TNF-α activity, or eliminating Kupffer cells in the experimental animal models. The researchers are further investigating the potential of implementing these strategies in human patients to block these remote effects of tumors on the liver and exploring the possibility of utilizing the detection of palmitic acid in tumor EVPs circulating in the blood as a potential warning sign of advanced cancer.
Reference: “Tumour extracellular vesicles and particles induce liver metabolic dysfunction” by Gang Wang, Jianlong Li, Linda Bojmar, Haiyan Chen, Zhong Li, Gabriel C. Tobias, Mengying Hu, Edwin A. Homan, Serena Lucotti, Fengbo Zhao, Valentina Posada, Peter R. Oxley, Michele Cioffi, Han Sang Kim, Huajuan Wang, Pernille Lauritzen, Nancy Boudreau, Zhanjun Shi, Christin E. Burd, Jonathan H. Zippin, James C. Lo, Geoffrey S. Pitt, Jonathan Hernandez, Constantinos P. Zambirinis, Michael A. Hollingsworth, Paul M. Grandgenett, Maneesh Jain, Surinder K. Batra, Dominick J. DiMaio, Jean L. Grem, Kelsey A. Klute, Tanya M. Trippett, Mikala Egeblad, Doru Paul, Jacqueline Bromberg, David Kelsen, Vinagolu K. Rajasekhar, John H. Healey, Irina R. Matei, William R. Jarnagin, Robert E. Schwartz, Haiying Zhang and David Lyden, 24 May 2023, Nature.
DOI: 10.1038/s41586-023-06114-4

News
Unlocking hidden soil microbes for new antibiotics
Most bacteria cannot be cultured in the lab-and that's been bad news for medicine. Many of our frontline antibiotics originated from microbes, yet as antibiotic resistance spreads and drug pipelines run dry, the soil [...]
By working together, cells can extend their senses beyond their direct environment
The story of the princess and the pea evokes an image of a highly sensitive young royal woman so refined, she can sense a pea under a stack of mattresses. When it comes to [...]
Overworked Brain Cells May Hold the Key to Parkinson’s
Scientists at Gladstone Institutes uncovered a surprising reason why dopamine-producing neurons, crucial for smooth body movements, die in Parkinson’s disease. In mice, when these neurons were kept overactive for weeks, they began to falter, [...]
Old tires find new life: Rubber particles strengthen superhydrophobic coatings against corrosion
Development of highly robust superhydrophobic anti-corrosion coating using recycled tire rubber particles. Superhydrophobic materials offer a strategy for developing marine anti-corrosion materials due to their low solid-liquid contact area and low surface energy. However, [...]
This implant could soon allow you to read minds
Mind reading: Long a science fiction fantasy, today an increasingly concrete scientific goal. Researchers at Stanford University have succeeded in decoding internal language in real time thanks to a brain implant and artificial intelligence. [...]
A New Weapon Against Cancer: Cold Plasma Destroys Hidden Tumor Cells
Cold plasma penetrates deep into tumors and attacks cancer cells. Short-lived molecules were identified as key drivers. Scientists at the Leibniz Institute for Plasma Science and Technology (INP), working with colleagues from Greifswald University Hospital and [...]
This Common Sleep Aid May Also Protect Your Brain From Alzheimer’s
Lemborexant and similar sleep medications show potential for treating tau-related disorders, including Alzheimer’s disease. New research from Washington University School of Medicine in St. Louis shows that a commonly used sleep medication can restore normal sleep patterns and [...]
Sugar-Coated Nanoparticles Boost Cancer Drug Efficacy
A team of researchers at the University of Mississippi has discovered that coating cancer treatment carrying nanoparticles in a sugar-like material increases their treatment efficacy. They reported their findings in Advanced Healthcare Materials. Over a tenth of breast [...]
Nanoparticle-Based Vaccine Shows Promise in Fighting Cancer
In a study published in OncoImmunology, researchers from the German Cancer Research Center and Heidelberg University have created a therapeutic vaccine that mobilizes the immune system to target cancer cells. The researchers demonstrated that virus peptides combined [...]
Quantitative imaging method reveals how cells rapidly sort and transport lipids
Lipids are difficult to detect with light microscopy. Using a new chemical labeling strategy, a Dresden-based team led by André Nadler at the Max Planck Institute of Molecular Cell Biology and Genetics (MPI-CBG) and [...]
Ancient DNA reveals cause of world’s first recorded pandemic
Scientists have confirmed that the Justinian Plague, the world’s first recorded pandemic, was caused by Yersinia pestis, the same bacterium behind the Black Death. Dating back some 1,500 years and long described in historical texts but [...]
“AI Is Not Intelligent at All” – Expert Warns of Worldwide Threat to Human Dignity
Opaque AI systems risk undermining human rights and dignity. Global cooperation is needed to ensure protection. The rise of artificial intelligence (AI) has changed how people interact, but it also poses a global risk to human [...]
Nanomotors: Where Are They Now?
First introduced in 2004, nanomotors have steadily advanced from a scientific curiosity to a practical technology with wide-ranging applications. This article explores the key developments, recent innovations, and major uses of nanomotors today. A [...]
Study Finds 95% of Tested Beers Contain Toxic “Forever Chemicals”
Researchers found PFAS in 95% of tested beers, with the highest levels linked to contaminated local water sources. Per- and polyfluoroalkyl substances (PFAS), better known as forever chemicals, are gaining notoriety for their ability [...]
Long COVID Symptoms Are Closer To A Stroke Or Parkinson’s Disease Than Fatigue
When most people get sick with COVID-19 today, they think of it as a brief illness, similar to a cold. However, for a large number of people, the illness doesn't end there. The World [...]
The world’s first AI Hospital, developed in China is transforming healthcare
Artificial Intelligence and its developments have had a revolutionary impact on society, and healthcare is not an exception. China has made massive strides in AI integrated healthcare, and continues to do so as AI [...]