Emergence of invasive pathobionts in gut microbiome promotes cancer stemness via targeting Hippo pathways.
Journal
Gut microbes
Journal Volume
18
Journal Issue
1
ISSN
1949-0984
Date Issued
2026-12-31
Author(s)
Yu, Linda Chia-Hui
Wei, Shu-Chen
Li, Yi-Hsuan
Lin, Been-Ren
Liao, Yu-Chien
Peng, Yu-Wen
Lin, Chia-Hsien
Hu, Pei-Tzu
Pai, Yu-Chen
Huang, Chung-Yen
Chen, You-Tzung
Lai, Liang-Chuan
Jeng, Yung-Ming
Abstract
Growing evidence suggests a pivotal role of the microbiome in tumorigenesis, extending beyond genetics. Apc(Min/+) mice exhibit reduced tumor load when housed in germ-free conditions. Nevertheless, how genetic factors shape microbiota and how dysbiosis fits into the genetic paradigm of intestinal carcinogenesis remain elusive. Epithelial stemness is regulated by Wnt/Apc/β-catenin pathway, whereas mutations and Hippo signaling are associated with tumor growth. Invasive pathobionts emerge from microbiota as a result of epithelial barrier dysfunction. We hypothesize that the emergence of invasive pathobionts and dysbiosis of epithelial microbiota contribute to increased cancer stemness. The epithelial and fecal microbiota are longitudinally monitored in Apc(Min/+) and wild-type littermates born to wild-type surrogate dams. Segregation of epithelial microbiota between Apc(Min/+) and wild-type mice was observed as early as eight weeks after birth, whereas fecal microbiota diverged at 20 weeks of age. Epithelial dysbiosis and barrier defects were observed in Apc(Min/+) mice, characterized by intraepithelial with invasive features. While antibiotic treatment reduced cancer burden, invasive infection promoted tumorsphere formation. Higher expression of and (Hippo effectors) and (a cancer stemness marker) was observed in bacteria-infected tumorspheres. Mechanistically, bacteria augmented epithelial clonogenicity by enhancing VGLL3/TEAD4-mediated CD44 promoter activity. Invasive genetic signatures were verified in 86% of human colorectal carcinoma specimens, and a positive correlation with TEAD4 expression was observed. In conclusion, mutation drives the expansion of invasive pathobionts to promote cancer stemness via a VGLL3/TEAD4/CD44 axis. Bacteria-targeting interventions could be an alternative strategy for patients with hereditary tumors.
Subjects
Colorectal cancer microbiome
Hippo signaling
clonogenicity
experimental pathobiont models
hereditary cancer
intestinal epithelial cells
invasive pathobionts
stem cells
tumorigenic E. coli
tumorsphere
Type
journal article