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.
[1]Wuhan Univ, Zhongnan Hosp, Hubei Canc Clin Study Ctr, Dept Radiat & Med Oncol, Wuhan, Peoples R China.
[2]Wuhan Univ, Zhongnan Hosp, Hubei Key Lab Tumor Biol Behav, Wuhan, Peoples R China.
[3]Fudan Univ, Shanghai Canc Ctr, Dept Urol, Shanghai, Peoples R China.
[4]Fudan Univ, Shanghai Med Coll, Dept Oncol, Shanghai, Peoples R China.
[5]Peking Univ, Kunming Med Univ, Affiliated Hosp 3,Canc Hosp Yunnan, Dept Radiotherapy,Yunnan Canc Hosp, Kunming, Peoples R China.
[6]Southern Med Univ, Nanfang Hosp, Dept Urol, Guangzhou, Peoples R China.
(8.0+极速模式)