Blocking cholesterol pathways slows tumor growth by 65% in mice

A research team from the LKS Faculty of Medicine at the University of Hong Kong (HKUMed) has made a breakthrough in gastric cancer research, revealing how the “second brain”—nerves in the digestive system, also known as enteric neurons—influences tumor growth and treatment responses.

The study reveals that these enteric neurons increase gastric cancer cells’ reliance on lipids (i.e., fatty acids and cholesterol) for survival. When cancer cells are infiltrated by neurons, targeting this metabolic vulnerability with cholesterol pathway inhibitors can enhance cancer cell death by 6.3 times.

This discovery opens new avenues for developing personalized therapies for gastric cancer. The findings were published in the journal Cell Stem Cell.

Targeting lipid metabolism vulnerabilities slows tumor growth by 65%

Gastric cancer is one of the world’s deadliest cancers, often diagnosed at advanced stages with low survival rates. Beyond the cancer cells themselves, tumors interact with surrounding tissues. Enteric neurons, in particular, which regulate digestive function, were found to fuel cancer growth.

The HKUMed research team used a gene-editing platform to scan approximately 20,000 genes in gastric cancer cells, identifying two factors involved in lipid metabolism—ACACA and LSS—which regulate fatty acids and cholesterol metabolic pathways, respectively.

These two factors serve as the ‘power plants’ of cancer cells, helping them produce lipids to sustain growth. In mouse models, blocking these factors with inhibitors slowed tumor growth by about 65%, on average.

Furthermore, the research team developed a model that simulates the interaction between enteric neurons and gastric cancer tumors by co-culturing enteric neurons with gastric cancer organoids, replicating the scenario in which patients’ cancer cells are infiltrated by neurons.

The results revealed elevated fatty acid metabolism levels within cancer cells, indicating their heightened lipid dependency. When cholesterol inhibitors were applied, the efficacy of killing cancer cells increased 6.3-fold.

From mechanism discovery to precision therapy

“Our study shows how gut nerves can make gastric cancers hungrier for fats, and these cells are vulnerable to cholesterol pathway inhibitors,” said Professor Alan Wong Siu-lun, Associate Professor, School of Biomedical Sciences, HKUMed, who led the study.

“This discovery will help in the development of new gastric cancer drugs and establish predictive methods for understanding patients’ treatment responses. It also highlights the importance of targeting the interactions between neurons and cancer cells as a therapeutic strategy.”

Professor Leung Suet-yi, chairperson of the Department of Pathology, School of Clinical Medicine, HKUMed, who co-led the research, added, “By conducting genetic screening using organoids cultured from the tissues of gastric cancer patients, our research team revealed how the body’s second brain—enteric neurons in the digestive system—influences the metabolic vulnerabilities of gastric cancer cells.

“This discovery deepens our understanding of the mechanism of cancer cell growth and opens new avenues for developing precision therapies targeting gastric cancer.”

“Identifying fatty acid metabolic factors as potential biomarkers will enable doctors to match patients with the most suitable treatment plans more accurately and effectively in the future, improving therapeutic outcomes and success rates,” added Professor Wong.

“The approach is not limited to gastric cancer; it also holds potential for applications in other cancers in which nerves play a role, such as pancreatic cancer and liver cancer, offering new perspectives for research into the tumor microenvironment.”

This discovery identified lipid metabolism as a promising target for anti-gastric cancer drugs and has laid a foundation for developing a biomarker system for predicting therapeutic responses.

The research team has applied for a patent based on these findings and will extend the model to other cancer types, opening the door for innovative breakthroughs in precision cancer therapy.