2. Academic Validation
  3. A combined enteric neuron-gastric tumor organoid reveals metabolic vulnerabilities in gastric cancer

A combined enteric neuron-gastric tumor organoid reveals metabolic vulnerabilities in gastric cancer

  • Cell Stem Cell. 2025 Oct 2;32(10):1595-1613.e10. doi: 10.1016/j.stem.2025.08.006.
Becky K C Chan 1,  Chu Zhang 1,  Chi Him Poon 1,  Marie H Y Lee 1,  Hoi Yee Chu 1,  Bei Wang 1,  Sin-Guang Chen 1,  Helen H N Yan 2,  Suet Yi Leung 3,  Alan S L Wong 4
Affiliations

Affiliations

  • 1 Centre for Oncology and Immunology, Hong Kong Science Park, Pak Shek Kok, Hong Kong SAR, China; Laboratory of Combinatorial Genetics and Synthetic Biology, School of Biomedical Sciences, The University of Hong Kong, Pokfulam, Hong Kong SAR, China.
  • 2 Centre for Oncology and Immunology, Hong Kong Science Park, Pak Shek Kok, Hong Kong SAR, China; Department of Pathology, School of Clinical Medicine, The University of Hong Kong, Queen Mary Hospital, Pokfulam, Hong Kong SAR, China. Electronic address: yanhelen@hku.hk.
  • 3 Centre for Oncology and Immunology, Hong Kong Science Park, Pak Shek Kok, Hong Kong SAR, China; Department of Pathology, School of Clinical Medicine, The University of Hong Kong, Queen Mary Hospital, Pokfulam, Hong Kong SAR, China; Centre for PanorOmic Sciences, LKS Faculty of Medicine, The University of Hong Kong, Pokfulam, Hong Kong SAR, China. Electronic address: suetyi@hku.hk.
  • 4 Centre for Oncology and Immunology, Hong Kong Science Park, Pak Shek Kok, Hong Kong SAR, China; Laboratory of Combinatorial Genetics and Synthetic Biology, School of Biomedical Sciences, The University of Hong Kong, Pokfulam, Hong Kong SAR, China. Electronic address: aslw@hku.hk.
PMID: 40902593 DOI: 10.1016/j.stem.2025.08.006
Abstract

The discrepancy between Organoid and immortalized cell line cultures for Cancer target discovery remains unclear. Here, our multi-tiered clustered regularly interspaced short palindromic repeats (CRISPR) screens reveal in vivo-relevant metabolic dependencies and synthetic lethal pairs that can be uncovered with tumor organoids but not cell lines or even three-dimensional (3D) spheroids. These screens identify lanosterol synthase and acetyl-coenzyme A (CoA) carboxylase inhibitors as effective treatments that impede xenografted tumor growth in mice. These lipid metabolic inhibitors exhibit nanomolar half-maximal inhibitory concentration (IC50) values across diverse human gastric Cancer organoids resistant to first-line treatments. Mechanistically, gastric Cancer organoids and in vivo tumors exhibit lipid metabolic adaptations not seen in two-dimensional (2D) in vitro cultures. Additionally, enteric neurons modulate lipid metabolism in tumor organoids, altering drug sensitivity by up to two orders of magnitude. A neuron-cocultured CRISPR screen further reveals that Acetyl-CoA Carboxylase expression determines lanosterol synthase inhibitor efficacy. These findings highlight the critical roles of Organoid environment and neuronal interaction in Cancer lipid reliance.

Keywords

CRISPR screen; cancer neuroscience; cholesterol; coculture; enteric neuron; fatty acid; gastric cancer; lipid metabolism; organoid; tumor vulnerability.

Figures
Products
嗨！很高兴为您提供帮助！

尊敬的 MCE 客户您好，
请您选择所在区域，我们将转接对应客服为您服务！

热门区域

A

B

C

F

G

H

J

L

N

Q

S

T

X

Y

Z

热 A B C F G H J L N Q S T X Y Z