Understanding of how gut nerves influence gastric cancer treatment, paving way for new targeted therapies

Photos by: LKS Faculty of Medicine, HKU

A research team from the Centre for Oncology and Immunology (COI) and the LKS Faculty of Medicine at the University of Hong Kong (HKUMed) has made a breakthrough in understanding gastric cancer by revealing how nerves in the digestive system—known as enteric neurons—affect tumor growth and response to treatments. Using advanced 3D models of patient tumors and gene-editing tools, the team identified key weaknesses in gastric cancer cells related to lipid processing, suggesting drugs targeting this could improve outcomes. The findings also highlight how the gut nerves make the cancers more dependent on lipids, altering how well certain drug inhibitors work. This work, published in the journal Cell Stem Cell, opens doors to personalized therapies and has led to a patent application.

Background

Gastric cancer is one of the world’s deadliest cancers, affecting millions and often diagnosed at advanced stages with poor survival rates. Beyond just cancer cells, tumors interact with surrounding tissues, including nerves that control digestion. Recent studies suggest these enteric neurons—the “gut’s brain”—can fuel cancer growth. The COI and HKUMed team developed a research model mimicking these interactions to uncover new treatment strategies, focusing on identifying druggable targets that enable therapeutic development for better results.

Research Findings

The researchers used cutting-edge gene-editing platform to scan approximately twenty thousand genes in tumor models, pinpointing two factors—ACACA and LSS—involved in lipid metabolism that are vital for cancer survival. Blocking these with inhibitors slowed tumor growth in lab models, indicating potential new drugs. The study also explores how nerves promote this lipid dependency, suggesting that targeting nerve-cancer interactions could enhance drug effectiveness. Importantly, when enteric neurons were present—simulating how cancers invade nerves in patients—the tumors expressed more ACACA and became more sensitive to LSS inhibitor treatment. This revealed that neurons induced higher lipid reliance in cancer and changed their sensitivity to lipid inhibitor treatments. These findings point to combining nerve-modulating approaches with lipid-targeting drugs to facilitate the development for tailored therapies.

Significance of the Study

This discovery emphasizes lipid metabolism as a promising target for anti-gastric cancer drugs, potentially leading to new treatments that are more effective when considering nerve influences. By identifying ACACA as a potential biomarker, patients could be better matched to the right type of therapies, improving success rates. The approach could extend to other cancers where nerves play a role, offering broader insights into fighting tumors by disrupting their supportive environments.

“Our work shows how gut nerves can make gastric cancers hungrier for fats, making them vulnerable to specific inhibitors,” said Professor Alan Wong Siu Lun, Principal Investigator in COI and Associate Professor in the School of Biomedical Sciences, HKUMed, who led the research. “This could lead to new drugs and ways to predict which patients would respond best. And it highlights the importance to target nerve-cancer crosstalk and to apply our research model to other types of cancer for therapeutic purposes.’

About the Research Team

The study was led by Professor Alan Wong Siu Lun from COI and the School of Biomedical Sciences, and Professor Leung Suet Yi and Professor Helen Yan Hoi Ning from COI and the Department of Pathology. Co-first authors include Dr Becky Chan Ka Ching, Dr Zhang Chu, and Dr Poon Chi Him from the School of Biomedical Sciences and Centre for Oncology and Immunology, supported by Marie Lee Hiu Yan from the same center, and Dr Chu Hoi Yee, Dr Wang Bei, and Dr Chen Sin-Guang from the School of Biomedical Sciences.