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

ABSTRACT Colorectal cancer (CRC) lethality is largely driven by liver metastasis and the associated tumor microenvironment (TME). This study identifies ETS variant transcription factor 4 (ETV4) as a central integrator of oncogenic signaling, metabolism, and stromal remodeling. In CRC cells, hepatocyte growth factor (HGF)/MET signaling induces ETV4 via an ERK1/2–p65 pathway. ETV4, in turn, directly activates MET and asparagine synthetase (ASNS), creating a positive feedback loop that amplifies MET signaling and elevates intracellular asparagine (Asn). Tumor‐derived Asn acts as a paracrine signal that induces inflammatory cancer‐associated fibroblast (iCAF) like activation in hepatic stellate cells (HSCs) and promotes iCAF polarization in primary CAFs, leading to enhanced HGF secretion that further stimulates MET + tumor cells. Genetic and pharmacologic disruption of this axis attenuates CRC growth and metastatic traits in vitro and in mouse models. Notably, combined inhibition of HGF/MET signaling and Asn metabolism produces greater antitumor activity than either monotherapy. Together, these data delineate an HGF/MET → ETV4 → MET/ASNS → asparagine → iCAFs and iCAF‐like HSCs → HGF circuit that links signal amplification, metabolic reprogramming, and niche conditioning, and provide a rationale for therapeutic strategies co‑targeting HGF/MET and Asn pathways in advanced CRC.