ALKBH5 in Cancer-associated Fibroblasts Facilitates Pancreatic Cancer Metastasis via HSF1–LIF Axis [RIP-seq]

Here, using both primary and immortalized CAFs that we established from patient-derived samples, we identified m6A demethylase AlkB homolog 5 (ALKBH5) as a critical regulator of CAF-driven PDAC metastasis.

We show that CAF activation induces a global reduction in m6A levels, with ALKBH5 emerging as a core modulator of the m6A epitranscriptome. Mechanistically, ALKBH5 enhances the m6A-dependent translational efficiency of heat shock factor 1 (HSF1), which in turn activates leukemia inhibitory factor (LIF) transcription by binding to its enhancer elements. Paracrine LIF signaling promotes epithelial–mesenchymal transition in pancreatic cancer cells, thereby facilitating tumor metastasis to the liver and lungs.