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<p>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 <i>GAD1</i> and low expression of <i>ABAT</i>, 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 <i>GAD1</i> expression correlates with increased metastatic potential. Knockdown and pharmacological inhibition of <i>GAD1</i> 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.</p><p></p>

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GABAergic signaling contributes to tumor cell invasion and poor overall survival in colorectal cancer

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2025年8月24日

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  • Carly Strelez,
  • Francesca Battaglin,
  • Rachel Perez,
  • Yan Yang,
  • Christopher Cherry,
  • Joshua Millstein,
  • Ah Young Yoon,
  • John S. Chlystek,
  • Ethan Canfield,
  • Bethany Haliday,
  • Curran Shah,
  • Kimya Ghaffarian,
  • Shivani Soni,
  • Hannah Jiang,
  • Roy Lau,
  • Aaron Schatz,
  • Yuyuan Zhou,
  • Daniel Mulkerin,
  • Fang-Shu Ou,
  • Alan P. Venook,
  • Federico Innocenti,
  • Josh Neman,
  • Jonathan E. Katz,
  • Heinz-Josef Lenz,
  • Shannon M. Mumenthaler

摘要

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.