Obeid, J. | bioRxiv Science

bioRxiv2026

Neutral Sphingomyelinase-2 Restrains TAZ to Suppress Breast Tumor Growth

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 the 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.

cancer biology↗

bioRxiv2026

Metabolic plasticity of sphingolipids governs cancer cell fitness in acidic tumor ecosystems

Cell state plasticity enables cancer cells to rapidly adapt to fluctuating microenvironments without requiring genetic alteration, shaping tumor evolution under stress. Extracellular acidosis is a persistent feature of solid tumors that impose strong selective pressure, yet how cancer cells maintain fitness under acute and chronic acidic conditions remains unclear. Here, we show that adaptation to acidosis is mediated by plastic rewiring of sphingolipid metabolism centered on ceramide turnover. Spatial multi-omics analysis of three-dimensional tumor models revealed enrichment of ceramides within acidic niches, consistent with a stress-induced phenotype. While acute acidosis promoted ceramide accumulation and reduced fitness, chronic exposure selected for cells capable of dynamically redistributing sphingolipid flux across multiple clearance pathways. Functional perturbation demonstrated that inhibition of individual pathways was insufficient to compromise survival, whereas simultaneous disruption of all ceramide clearance routes resulted in cell death, revealing a degenerate metabolic architecture. This network-level flexibility enables cancer cells to maintain fitness by switching between alternative metabolic states under acidic stress. Together, our findings identify sphingolipid metabolic plasticity as an adaptive strategy that supports tumor persistence in acidic ecosystems and suggest that targeting metabolic flexibility, rather than individual pathways, may provide a more effective therapeutic approach.

cancer biology↗