@article{6066,
  keywords = {Cancer microenvironment, Cancer models, colorectal cancer},
  author = {Carly Strelez and Francesca Battaglin and Rachel Perez and Yan Yang and Christopher Cherry and Joshua Millstein and Ah Young Yoon and John S. Chlystek and Ethan Canfield and Bethany Haliday and Curran Shah and Kimya Ghaffarian and Shivani Soni and Hannah Jiang and Roy Lau and Aaron Schatz and Yuyuan Zhou and Daniel Mulkerin and Fang-Shu Ou and Alan P. Venook and Federico Innocenti and Josh Neman and Jonathan E. Katz and Heinz-Josef Lenz and Shannon M. Mumenthaler},
  title = {GABAergic signaling contributes to tumor cell invasion and poor overall survival in colorectal cancer},
  abstract = {Alterations in neurotransmitter signaling can influence colorectal cancer (CRC). In a large, randomized Phase III clinical trial (CALGB/SWOG 80405) involving patients with metastatic CRC, high expression of gamma-aminobutyric acid (GABA) pathway gene GAD1 and low expression of ABAT, indicative of a GABAergic environment, were associated with worse progression-free survival and overall survival outcomes. A metastasis map of human cancer cell lines (MetMap) and functional studies using a microfluidic tumor-on-chip platform demonstrated that high GAD1 expression correlates with increased metastatic potential. Knockdown and pharmacological inhibition of GAD1 reduced tumor invasion, while exogenous GABA promoted invasion. Tumor-derived GABA was elevated in Ras-altered tumors. Furthermore, analysis of publicly available data confirmed that higher GAD1 expression is associated with worse outcomes in Ras-mutant tumors. These findings establish a role for GABA signaling in tumor invasiveness, particularly in Ras-altered CRC. This study demonstrates using clinical data to inform new discoveries and highlights the need for advanced preclinical model systems that more accurately reflect human physiology to explore these findings.},
  year = {2025},
  journal = {Oncogene},
  pages = {1-15},
  month = {2025-08-24},
  issn = {1476-5594},
  url = {https://www.nature.com/articles/s41388-025-03546-2},
  doi = {10.1038/s41388-025-03546-2},
  language = {en},
}