TY - JOUR
KW - Cancer microenvironment
KW - Cancer models
KW - colorectal cancer
AU - Carly Strelez
AU - Francesca Battaglin
AU - Rachel Perez
AU - Yan Yang
AU - Christopher Cherry
AU - Joshua Millstein
AU - Ah Young Yoon
AU - John S. Chlystek
AU - Ethan Canfield
AU - Bethany Haliday
AU - Curran Shah
AU - Kimya Ghaffarian
AU - Shivani Soni
AU - Hannah Jiang
AU - Roy Lau
AU - Aaron Schatz
AU - Yuyuan Zhou
AU - Daniel Mulkerin
AU - Fang-Shu Ou
AU - Alan P. Venook
AU - Federico Innocenti
AU - Josh Neman
AU - Jonathan E. Katz
AU - Heinz-Josef Lenz
AU - Shannon M. Mumenthaler
AB - 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.
BT - Oncogene
DA - 2025-08-24
DO - 10.1038/s41388-025-03546-2
LA - en
N2 - 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.
PY - 2025
SP - 1
EP - 15
T2 - Oncogene
TI - GABAergic signaling contributes to tumor cell invasion and poor overall survival in colorectal cancer
UR - https://www.nature.com/articles/s41388-025-03546-2
Y2 - 2025-09-19
SN - 1476-5594
ER -