Sphingolipid Alterations and Adaptive Biology: Exploring the Metabolic Determinants of C6-Ceramide Nanoliposome Induced Organelle Stress in Cancer 45 views

Sphingolipids represent a unique class of molecules with both structural and signaling functions – playing direct and indirect roles in nearly every cellular process. Despite their central role, these lipids remain incompletely understood, especially in the context of cancer biology and treatment. In this work, I explore how these lipids can be therapeutically exploited in multiple cancer models using a ceramide containing nanoliposome (CNL). Interestingly, we see that accumulation of glycosphingolipids (GSLs), a metabolite of ceramide, not ceramide itself, drives anti-cancer activity of these nanoparticles. Mechanistically, we find that GSL accumulation leads to time-dependent disruption of multiple organelle systems, with lysosome deacidification followed by ER-stress induction followed by mitochondrial dysfunction and cell death. Importantly, pharmacologic and molecular blockade of GSL accumulation protects from CNL induced defects. The stress sensor JNK often serves to integrate sustained stress signals into cell death pathway activation, and we find that inhibition of this pathway partially protects from CNL mediated death. We also leverage this CNL-mediated induction of cell stress to uncover synergistic activity with DT-061, a small-molecule activator of protein phosphatase 2A and extend these findings to primary chronic lymphocytic leukemia patient samples. Taken together, this work demonstrates therapeutic potential of sphingolipids and further defines the mechanisms by which they accomplish these effects, uncovering an unexpected link between GSLs and cell death.

PHD (Doctor of Philosophy)

Cancer Metabolism; Therapeutics; nanomedicine; sphingolipids

English

2026-09-27