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ETV4 Promotes Colorectal Cancer Progression by Reprogramming Asparagine Metabolism to Remodel the Stromal

Dujiang Fu1, Meijia Zhang1, Maoping Cai2,3

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This study reveals how ETS variant transcription factor 4 (ETV4) drives colorectal cancer (CRC) liver metastasis by linking signaling, metabolism, and the tumor microenvironment. Targeting ETV4 and asparagine pathways offers new therapeutic strategies for advanced CRC.

Keywords:
ETV4HGF/MET signalingasparagine metabolismcolorectal cancerstromal microenvironment

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Area of Science:

  • Oncology
  • Molecular Biology
  • Cancer Metastasis

Background:

  • Colorectal cancer (CRC) liver metastasis is a major cause of mortality.
  • The tumor microenvironment (TME) plays a critical role in metastasis.
  • Understanding molecular drivers of CRC metastasis is crucial for developing effective therapies.

Purpose of the Study:

  • To identify key regulators integrating oncogenic signaling, metabolism, and stromal remodeling in CRC liver metastasis.
  • To elucidate the role of ETS variant transcription factor 4 (ETV4) in the HGF/MET signaling pathway and its impact on the TME.
  • To explore therapeutic strategies targeting the identified pathway in advanced CRC.

Main Methods:

  • Investigated the role of ETV4 in CRC cells using hepatocyte growth factor (HGF)/MET signaling.
  • Analyzed the positive feedback loop involving ETV4, MET, and asparagine synthetase (ASNS).
  • Assessed the impact of tumor-derived asparagine on cancer-associated fibroblasts (CAFs) and hepatic stellate cells (HSCs).
  • Utilized in vitro and in vivo mouse models to evaluate genetic and pharmacologic interventions.
  • Compared the efficacy of combined HGF/MET and asparagine metabolism inhibition against monotherapy.

Main Results:

  • ETV4 acts as a central integrator, induced by HGF/MET signaling via ERK1/2-p65.
  • ETV4 amplifies MET signaling and elevates intracellular asparagine (Asn) by activating MET and ASNS.
  • Tumor-derived Asn promotes iCAF-like activation in HSCs and iCAF polarization, increasing HGF secretion.
  • Disrupting the HGF/MET → ETV4 → MET/ASNS → asparagine → iCAFs/HSCs → HGF axis attenuated CRC growth and metastasis.
  • Combined inhibition of HGF/MET and Asn metabolism demonstrated superior antitumor activity.

Conclusions:

  • The HGF/MET-ETV4-ASNS axis drives CRC liver metastasis through signal amplification, metabolic reprogramming, and niche conditioning.
  • ETV4 is a key mediator linking oncogenic signaling, metabolic alterations, and stromal interactions in CRC.
  • Co-targeting HGF/MET signaling and asparagine metabolism presents a promising therapeutic strategy for advanced CRC.