ETV7 drives 5-FU resistance and colorectal cancer progression by upregulating CXCL1 and inducing NETs formation

Colorectal cancer (CRC) remains a significant global health challenge, with 5-fluorouracil (5-FU) as a cornerstone chemotherapy. However, widespread 5-FU resistance severely limits treatment efficacy and contributes to disease progression. Understanding the molecular mechanisms driving this resistance is crucial for developing more effective therapeutic strategies. This study investigates novel pathways contributing to CRC chemoresistance and malignancy, focusing on transcriptional regulators and their impact on the tumor microenvironment.

Researchers identified ETS variant transcription factor 7 (ETV7) as significantly upregulated in CRC tissues and cell lines. They conducted in vitro functional assays to assess the impact of ETV7 on CRC cell proliferation, invasion, and 5-FU resistance. In vivo models were employed to further validate ETV7's role in tumor aggressiveness and chemoresistance. Mechanistic studies utilized gene expression analysis to investigate ETV7's transcriptional targets, specifically focusing on CXCL1 and its downstream effects on neutrophil recruitment and NETs formation. Pharmacological interventions, including CXCL1 inhibitors and NETs degraders, were tested to attenuate ETV7-driven malignant phenotypes.

ETV7 was found to be significantly upregulated in CRC tissues and cell lines, with its elevated expression correlating with a poor clinical prognosis. Functional assays demonstrated that ETV7 enhanced CRC cell proliferation, invasion, and resistance to 5-FU. Mechanistically, ETV7 transcriptionally upregulated CXCL1, which subsequently led to increased neutrophil recruitment within the tumor microenvironment. This increased recruitment resulted in enhanced formation of neutrophil extracellular traps (NETs). The resulting NETs-enriched tumor microenvironment was shown to promote tumor aggressiveness and chemoresistance.

Pharmacological inhibition of CXCL1 or degradation of NETs effectively attenuated ETV7-driven malignant phenotypes both in vitro and in vivo, suggesting a critical role for this axis in CRC progression.