FTO Enzyme Fuels Pancreatic Cancer Growth by Hijacking Cell Energy Metabolism

Pancreatic ductal adenocarcinoma (PDAC) remains one of the deadliest cancers, with a five-year survival rate of roughly 10%. Its resistance to chemotherapy, radiation, and targeted therapies partly stems from a highly adaptable tumor microenvironment and reprogrammed energy metabolism — specifically an aggressive reliance on glycolysis even in the presence of oxygen, known as the Warburg effect. Understanding the molecular regulators that drive this metabolic shift is critical for developing new treatments.

This study focused on FTO (fat mass and obesity-associated protein), an m6A RNA demethylase that removes N6-methyladenosine modifications from messenger RNA. Using a multiomics approach integrating metabolomics, m6A sequencing (m6A-seq), and transcriptome sequencing across three cohorts of PDAC patient tissues, the researchers found that FTO is significantly overexpressed in PDAC compared to normal pancreatic tissue. Higher FTO expression correlated with worse clinical outcomes.

Mechanistically, the team showed that FTO removes m6A marks from C-Jun mRNA, protecting it from recognition and degradation by the m6A reader protein YTHDF2. This stabilizes C-Jun protein levels. C-Jun, a transcription factor in the AP-1 family, then directly upregulates expression of PFKM (phosphofructokinase, muscle type), a rate-limiting enzyme in glycolysis. The result is enhanced glycolytic flux — measurable as increased extracellular acidification rate (ECAR), elevated ATP production, and greater lactate output — that fuels PDAC cell proliferation, migration, and invasion.

Functional validation was extensive. In vitro, FTO knockdown in MiaPaCa-2 and PANC-1 cells reduced PFKM expression, impaired glycolysis, and suppressed migration. In vivo, FTO conditional knockout in the aggressive KPC mouse model (LSL-Kras^G12D, LSL-Trp53^R172H, Pdx1-Cre) substantially slowed tumor development and reduced liver metastasis. Pancreatic organoids derived from KPC and FTO-knockout KPC (FKPC) mice confirmed these phenotypes ex vivo. Pharmacological inhibition with FB23-2, a selective FTO inhibitor, recapitulated genetic FTO loss in both xenograft tumor models and organoid cultures, significantly suppressing tumor growth.

These findings establish the FTO/C-Jun/PFKM axis as a previously unrecognized driver of PDAC metabolic reprogramming and offer a compelling rationale for developing FTO inhibitors as PDAC therapeutics. Given that glycolytic inhibition alone (e.g., with 2-DG) was also tested and showed additive effects, combination strategies targeting this axis warrant further investigation.