biostudies-literatureAbu Rmaileh AHebrew UniversityIsrael Science FoundationMorgridge Institute for ResearchIsrael Cancer Research Funde202106078https://www.ebi.ac.uk/biostudies/studies/S-EPMC9115587biostudies-literatureUnknown221(7)The intricate neuronal wiring during development requires cytoskeletal reorganization orchestrated by signaling cues. Because cytoskeletal remodeling is a hallmark of cell migration, we investigated whether metastatic cancer cells exploit axon guidance proteins to migrate. Indeed, in breast cancer patients, we found a significant correlation between mesenchymal markers and the expression of dihydropyrimidinase-like 2 (DPYSL2), a regulator of cytoskeletal dynamics in growing axons. Strikingly, DPYSL2 knockout in mesenchymal-like breast cancer cells profoundly inhibited cell migration, invasion, stemness features, tumor growth rate, and metastasis. Next, we decoded the molecular mechanism underlying this phenomenon and revealed an interaction between DPYSL2 and Janus kinase 1 (JAK1). This biThe Journal of cell biologyDPYSL2 interacts with JAK1 to mediate breast cancer cell migration.PMC91155871816/16299/21Khatib AAbu Rmaileh ATanna MBen Yosef MLichtenstein MLavi SSolaimuthu BHayashi AShaul YDPillar NfalseDPYSL2 interacts with JAK1 to mediate breast cancer cell migration.The intricate neuronal wiring during development requires cytoskeletal reorganization orchestrated by signaling cues. Because cytoskeletal remodeling is a hallmark of cell migration, we investigated whether metastatic cancer cells exploit axon guidance proteins to migrate. Indeed, in breast cancer patients, we found a significant correlation between mesenchymal markers and the expression of dihydropyrimidinase-like 2 (DPYSL2), a regulator of cytoskeletal dynamics in growing axons. Strikingly, DPYSL2 knockout in mesenchymal-like breast cancer cells profoundly inhibited cell migration, invasion, stemness features, tumor growth rate, and metastasis. Next, we decoded the molecular mechanism underlying this phenomenon and revealed an interaction between DPYSL2 and Janus kinase 1 (JAK1). This bi2022-01-01T00:00:00Z2022 Jul2025-04-05T12:10:18.742Z2025-04-05T12:10:18.742ZS-EPMC91155873557579810.1083/jcb.202106078