02494nas a2200469   4500000000100000000000100001008004100002260001500043653002800058653001800086653002200104100001800126700002400144700001700168700001300185700002300198700002100221700001800242700002100260700001900281700002000300700001600320700002100336700001700357700001700374700001200391700001700403700001600420700002000436700001600456700001900472700002300491700001500514700002100529700002100550700002700571245010600598856005500704300000900759520124200768022001402010       2025                            d  c2025-08-2410aCancer microenvironment10aCancer models10acolorectal cancer1 aCarly Strelez1 aFrancesca Battaglin1 aRachel Perez1 aYan Yang1 aChristopher Cherry1 aJoshua Millstein1 aAh Young Yoon1 aJohn S. Chlystek1 aEthan Canfield1 aBethany Haliday1 aCurran Shah1 aKimya Ghaffarian1 aShivani Soni1 aHannah Jiang1 aRoy Lau1 aAaron Schatz1 aYuyuan Zhou1 aDaniel Mulkerin1 aFang-Shu Ou1 aAlan P. Venook1 aFederico Innocenti1 aJosh Neman1 aJonathan E. Katz1 aHeinz-Josef Lenz1 aShannon M. Mumenthaler00aGABAergic signaling contributes to tumor cell invasion and poor overall survival in colorectal cancer  uhttps://www.nature.com/articles/s41388-025-03546-2  a1-153 aAlterations 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.  a1476-5594