Transfer RNA fragment rewires metabolism, fueling colorectal cancer's spread to liver

Liver metastasis is the leading cause of death in colorectal cancer, but the molecular events that allow tumour cells to spread and adapt to the liver remain incompletely understood.

A study published in Science Bulletin identifies tRF-Glu-TTC-013, a tRNA-derived fragment, as a key driver of colorectal cancer liver metastasis. The researchers found that the molecule promotes tumour progression by enhancing glutamate metabolic reprogramming through a newly defined CREB3L1–AMDHD1 pathway.

The team showed that tRF-Glu-TTC-013 is progressively upregulated from primary colorectal tumours to liver metastatic lesions and is significantly associated with poor patient prognosis. By integrating tRF sequencing with transcriptomic and metabolomic analyses, the researchers found that this noncoding RNA is closely linked to glutamate metabolic changes during metastatic progression.

Functional experiments demonstrated that tRF-Glu-TTC-013 increases glutamate production and promotes colorectal cancer cell proliferation, invasion and metastasis in vitro and in vivo. These findings suggest that the molecule is not only associated with disease progression, but also actively contributes to it.

Mechanistically, the researchers found that tRF-Glu-TTC-013 interacts with the transcription factor CREB3L1, enhancing its stability and increasing expression of AMDHD1, a key enzyme involved in glutamate anabolism. This newly identified tRF-Glu-TTC-013–CREB3L1–AMDHD1 axis reshapes metabolic flux in ways that support tumour growth and liver colonisation.

The findings reveal a previously unrecognised pathway linking a noncoding RNA to transcriptional regulation, metabolic remodelling and metastatic progression. The study suggests that this pathway may offer a potential therapeutic target for metastatic colorectal cancer.

The study was led by Yuhui Li of the Department of Pathology and the Department of Clinical Laboratory, Sun Yat-sen Memorial Hospital, Sun Yat-sen University. The corresponding authors are Jianming Li of the First Affiliated Hospital of Nanchang University and Wen Ni of the Department of Pathology, Sun Yat-sen Memorial Hospital, Sun Yat-sen University.

This study was supported by the National Natural Foundation of China (grant numbers U24A20726, 82273145, and 82130080), the Guangdong Basic and Applied Basic Research Foundation (2024A1515012816), and the Sun Yat-sen Pilot Scientific Research Fund (YXQH202614).