biostudies-literatureOmi JJapan Agency for Medical Research and DevelopmentJapan Science and Technology Agency Moonshot R&D ProgramJapan Society for the Promotion of Sciencee202212074https://www.ebi.ac.uk/biostudies/studies/S-EPMC10694799biostudies-literatureUnknown223(2)Cancer cells harness lipid metabolism to promote their own survival. We screened 47 cancer cell lines for survival dependency on phosphatidylserine (PS) synthesis using a PS synthase 1 (PTDSS1) inhibitor and found that B cell lymphoma is highly dependent on PS. Inhibition of PTDSS1 in B cell lymphoma cells caused a reduction of PS and phosphatidylethanolamine levels and an increase of phosphoinositide levels. The resulting imbalance of the membrane phospholipidome lowered the activation threshold for B cell receptor (BCR), a B cell-specific survival mechanism. BCR hyperactivation led to aberrant elevation of downstream Ca2+ signaling and subsequent apoptotic cell death. In a mouse xenograft model, PTDSS1 inhibition efficiently suppressed tumor growth and prolonged survival. Our findings suggest that PS synthesis may be a critical vulnerability of malignant B cell lymphomas that can be targeted pharmacologically.The Journal of cell biologyPhosphatidylserine synthesis controls oncogenic B cell receptor signaling in B cell lymphoma.PMC10694799JPMJMS2023-11JP21gm1210013JP22ck0106533h000322K15272JP21gm0010004h990521J00906JPMJMS2023-15Sawada KYoshihama YKono NOmi JKato TAoki JfalsePhosphatidylserine synthesis controls oncogenic B cell receptor signaling in B cell lymphoma.Cancer cells harness lipid metabolism to promote their own survival. We screened 47 cancer cell lines for survival dependency on phosphatidylserine (PS) synthesis using a PS synthase 1 (PTDSS1) inhibitor and found that B cell lymphoma is highly dependent on PS. Inhibition of PTDSS1 in B cell lymphoma cells caused a reduction of PS and phosphatidylethanolamine levels and an increase of phosphoinositide levels. The resulting imbalance of the membrane phospholipidome lowered the activation threshold for B cell receptor (BCR), a B cell-specific survival mechanism. BCR hyperactivation led to aberrant elevation of downstream Ca2+ signaling and subsequent apoptotic cell death. In a mouse xenograft model, PTDSS1 inhibition efficiently suppressed tumor growth and prolonged survival. Our findings suggest that PS synthesis may be a critical vulnerability of malignant B cell lymphomas that can be targeted pharmacologically.2024-01-01T00:00:00Z2024 Feb2026-05-28T16:27:13.933Z2025-04-05T15:53:00.713ZS-EPMC106947993804822810.1083/jcb.202212074