Resnick, A. E.; Franzi, V.; Ghandour, B. K.; Chiappone, S. B.; Lalanne, S.; Alexander, M. E.; Peperno, D. M.; Obeid, J.; Pritam, I.; Miranda, I. D.; Coant, N.; Airola, M. V.; Damaghi, M.; Velazquez, F. N.; Hannun, Y. A.; Clarke, C. J.

Loss of tumor suppressor gene (TSG) activity is pervasive across cancers and linked to worse clinical outcomes, yet therapeutic efforts aimed at restoring TSGs have remained elusive. One underexplored avenue to address this problem is the targeting of metabolic signaling pathways that actively enforce tumor suppressive programs. Ceramide (Cer), the central hub of the sphingolipid (SL) metabolic network, has long been thought to have tumor suppressive functions, though its mechanistic roles remain incompletely defined. Here, we identify neutral sphingomyelinase-2 (nSMase2) as a critical mediator of Cer-dependent tumor suppression. We show that nSMase2 is frequently suppressed in breast cancer (BC) and its restoration inhibits tumorigenesis. Biologically, this was linked to suppression of anchorage-independent growth (AIG) and to restraint of the HIPPO pathway effector TAZ, but not its paralog YAP. Taken together, these findings define a previously unrecognized metabolic tumor suppressor pathway, clarify ambiguities in both SL and HIPPO signaling networks, and highlight reactivation of nSMase2-Cer signaling as a potential therapeutic strategy in BC.