Cancer Treatment May Trigger Recurrence… Chinese Researchers Identify the “Senescence–NET–CCDC25” Axis

Chemotherapy induces hepatocyte senescence and the formation of neutrophil extracellular traps (NETs), awakening dormant pancreatic cancer cells and promoting liver metastasis, according to a study.

A research team led by professors Zhou Tianxing and Hao Jihui of Tianjin Medical University in China published the findings in the international journal Cancer Research on the 4th (local time).

Using a dormancy-tracking system, the researchers found that chemotherapy activates dormant disseminated tumor cells (DTCs) established in the liver through hepatocyte senescence followed by NET formation.

In human and mouse cohorts, adjuvant and neoadjuvant chemotherapy induced hepatocyte senescence, which led to TGF-β secretion and SMAD-dependent NETosis.

DNA derived from NETs bound to the receptor CCDC25 on the surface of dormant DTCs, activating PI3K–AKT signaling and reprogramming the DTCs into a lipid-rich, proliferative phenotype.

Genetic and pharmacologic blockade of NET formation, TGF-β signaling or CCDC25 function effectively suppressed DTC reactivation and liver metastasis. The anticancer efficacy of chemotherapy was maintained.

Clinically, patients with high serum NET-DNA levels showed pronounced hepatocyte senescence and DTC proliferation, and had lower survival rates across several solid tumors, including pancreatic ductal adenocarcinoma (PDAC).

The researchers said the findings identify a “senescence–NET–CCDC25” axis linking chemotherapy-induced tissue damage to metastatic recurrence and provide a basis for adjuvant and neoadjuvant strategies targeting NETosis and CCDC25.

Pancreatic ductal adenocarcinoma is a deadly cancer with a 5-year survival rate below 10%, and recurrence and distant metastasis remain common despite advances in surgery and systemic treatment. Chemotherapy remains a key treatment, but reports have continued to emerge that it increases the burden of metastasis after treatment in several cancer types, including breast, lung and colorectal cancers.

DTCs are cancer cells that detach from the primary tumor and settle in distant organs such as the bone marrow, lungs, liver and brain. In a dormant state, they do not divide and show strong resistance to conventional chemotherapy and radiation therapy. These dormant cells are known to serve as “seeds” of recurrence after tumor removal and adjuvant treatment.