Is your diet killing your DNA? Scientists discover ‘time bomb’ against liver cancer

Liver cells attempt to shut down as a defense mechanism against cancer, but this strategy is not particularly effective.

Researchers at the University of California San Diego School of Medicine have provided new information on the development of liver cancer, a disease that ranks as the sixth most commonly diagnosed cancer and the fourth leading cause of cancer-related deaths worldwide.

Their study, published in Naturehighlights a complex relationship between cellular metabolism and

” data-gt-translate-attributes=”({“attribute=”” tabindex=”0″ role=”link”>DNA damage that fuels the progression of fatty liver disease to liver cancer. These findings open new avenues to prevent and treat liver cancer while deepening our understanding of how cancer develops and the impact of diet on DNA.

Over the past 20 years, cases of hepatocellular carcinoma (HCC), the most common type of liver cancer, have increased by 25 to 30 percent. A significant factor in this increase is the growing prevalence of fatty liver disease, which now affects 25% of adults in the United States. About 20% of people with fatty liver disease develop a more severe form called metabolic dysfunction-associated steatohepatitis (MASH), which significantly increases the risk of HCC. Despite this, the mechanisms that lead to the progression of MASH to liver cancer remain poorly understood.

“Going from fatty liver disease to MASH to liver cancer is a very common scenario, and the consequences can be life-threatening,” said Michael Karin, Ph.D., professor emeritus in the Department of Pharmacology at the University School of Medicine. UC San Diego. “When you have MASH, you either end up destroying your liver and then need a new liver, or you progress to liver cancer which is often fatal, but we still don’t understand what’s happening at the subcellular level at the during this process.”

DNA damage and cellular senescence in the development of liver cancer

The researchers used a combination of mouse models, human tissue samples and databases to demonstrate that MASH-inducing diets, high in fat and sugar, cause DNA damage in the liver cells that cause them. lead to senescence, a state in which cells are still alive and metabolically active but can no longer divide.

Senescence is a normal response to various cellular stressors. In a perfect world, senescence gives the body time to repair damage or eliminate damaged cells before they can proliferate more widely and become cancerous.

However, as researchers discovered, this is not what happens in liver cells, also called hepatocytes. In hepatocytes, some damaged cells survive this process.

These cells are, according to Karin, “like time bombs that could start proliferating again at any time and ultimately become cancerous.”

“Comprehensive genomic analyzes of tumor DNA indicate that they originate from MASH-damaged liver cells, highlighting a direct link between diet-induced DNA damage and cancer development,” added the co- study author Ludmil Alexandrov, Ph.D., associate professor. in Cellular and Molecular Medicine and Bioengineering at UC San Diego and a member of the Moores Cancer Center at UC San Diego.

Potential therapeutic approaches and knowledge about aging

The results suggest that developing new drugs to prevent or reverse DNA damage could provide a promising therapeutic approach to preventing liver cancer, particularly in people with MASH.

“There are some possibilities for how this could be exploited in a future treatment, but it will take more time and research to explore these ideas,” Karin said. “One hypothesis is that a high-fat diet might lead to an imbalance in the raw materials our cells use to build and repair DNA, and that we might use drugs or nutrichemicals to correct these imbalances. Another idea is to develop new antioxidants, much more effective and specific than those we currently have, and their use could help block or reverse the cellular stress that causes DNA damage in the first place.

In addition to opening up these new avenues for treating liver cancer, the study also offers new insights into the relationship between aging and cancer.

“We know that aging increases the risk of virtually all cancers and that aging is associated with cellular senescence, but this introduces a paradox since senescence is thought to protect against cancer,” Karin said. “This study helps reveal the underlying molecular biology that allows cells to re-enter the cell cycle after undergoing senescence, and we believe that similar mechanisms could act in a wide range of cancers. »

The findings also help directly quantify the detrimental effects of poor diet on cellular metabolism, which Karin says could be used to guide public health messaging related to fatty liver disease.

“A poor diet, based on fast food, can be as dangerous as cigarettes in the long term,” Karin said. “People need to understand that a poor diet does more than just alter a person’s aesthetic appearance. They can fundamentally change the way our cells function, down to their DNA.

Reference: “FBP1 controls the progression of liver cancer from senescent MASH hepatocytes” by Li Gu, Yahui Zhu, Shuvro P. Nandi, Maiya Lee, Kosuke Watari, Breanna Bareng, Masafumi Ohira, Yuxiao Liu, Sadatsugu Sakane, Rodrigo Carlessi, Consuelo Sauceda, Debanjan Dhar, Souradipta Ganguly, Mojgan Hosseini, Marcos G. Teneche, Peter D. Adams, David J. Gonzalez, Tatiana Kisseleva, The Liver Cancer Collaborative, Janina EE Tirnitz-Parker, M. Celeste Simon, Ludmil B. Alexandrov and Michael Karin, December 32, 2024, Nature.
DOI: 10.1038/s41586-024-08317-9

Study co-authors include Li Gu, Yahui Zhu, Shuvro Nandi, Maiya Lee, Kosuke Watari, Breanna Bareng, Masafumi Ohira, Yuxiao Liu, Sadatsugu Sakane, Debanjan Dhar, Souradipta Ganguly, Mojgan Hosseini, Tatiana Kisseleva and Ludmil Alexandrov at UC. San Diego School of Medicine (Alexandrov is also a professor at the Jacobs School of Engineering at UC San Diego), Rodrigo Carlessi, The Liver Cancer Collaborative and Janina Tirnitz-Parker of the Curtin Health Innovation Research Institute, Consuelo Sauceda and David Gonzalez of the Skaggs School of Pharmacy and Pharmaceutical Sciences at UC San Diego, Marcos Teneche and Peter Adams at Sanford Burnham Prebys, and M. Celeste Simon at the Cancer Research Institute of the Abramson family. After completing their training at UC San Diego, Li Gu and Yahui Zhu completed one of the key experiments in their laboratory at West China Hospital in Chengdu, PRC.

This study was funded in part by the

” data-gt-translate-attributes=”({“attribute=”” tabindex=”0″ role=”link”>National Institutes of Health (grants R01DK120714, R01DK133448, R01CA234128, R01CA281784, P01CA281819, R01DK133448, R35CA220483, DK099205, (R01ES030993, R01ES032547, R01CA269919).