Naghibzadeh, K. | Search bioRxiv

bioRxiv2026

Autophagy Cholesterol Axis Remodeling Supports Malignant Progression and Chemoresistance in Glioma

Glioma progression and resistance to temozolomide (TMZ) remain major clinical challenges. Here, we investigated whether dysregulated autophagy and cholesterol metabolism are coordinately remodeled during glioma progression and TMZ resistance. Tissue microarray analysis of astrocytoma and glioblastoma specimens revealed progressive autophagosome accumulation, reflected by increased LC3{beta} puncta, coupled with impaired autophagic flux compared with adjacent normal brain tissue. These alterations intensified with tumor grade and were associated with upregulation of farnesyl diphosphate synthase (FDPS), linking malignant progression to cholesterol pathway remodeling. TMZ-resistant (R) glioblastoma cells exhibited epithelial-to-mesenchymal transition, mitotic quiescence, and mitochondrial remodeling consistent with a therapy-tolerant phenotype. Bioenergetic profiling demonstrated reduced respiratory reserve, diminished ATP-linked respiration, and elevated proton leak, indicating constrained metabolic flexibility. In parallel, impaired autophagy flux was associated with suppression of de novo cholesterol synthesis and transcriptional downregulation of SREBP-2 and LDL-R. Comprehensive lipidomic profiling revealed marked cholesterol metabolic reprogramming in R cells, characterized by accumulation of specific cholesteryl esters, including CE 22:5, CE 22:6, CE 22:4, and CE 20:4, despite reduced cholesterol biosynthesis. Pharmacologic inhibition of the mevalonate pathway with simvastatin significantly altered cholesteryl ester profiles but failed to restore autophagy flux or sensitize R cells to TMZ-induced apoptosis, even under combined TMZ-simvastatin treatment. Lay AbstractAs gliomas progress from astrocytoma to glioblastoma, autophagy becomes dysregulated and cholesterol metabolism is rewired. This coordinated remodeling supports tumor survival, metabolic plasticity, and resistance to temozolomide therapy. O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=133 SRC="FIGDIR/small/697885v2_ufig1.gif" ALT="Figure 1000"> View larger version (79K): org.highwire.dtl.DTLVardef@1183dd2org.highwire.dtl.DTLVardef@82e20dorg.highwire.dtl.DTLVardef@c6c8dforg.highwire.dtl.DTLVardef@adb427_HPS_FORMAT_FIGEXP M_FIG C_FIG HighlightsAutophagy flux blockade intensifies during progression from astrocytoma to glioblastoma Dysregulated autophagy is coupled to altered cholesterol metabolism in malignant gliomas TMZ-resistant glioblastoma cells undergo epithelial-to-mesenchymal transition and mitotic quiescence Resistant cells exhibit constrained bioenergetic capacity and mitochondrial remodeling Impaired autophagy suppresses de novo cholesterol synthesis and lipid recycling Lipidomics reveals accumulation of long-chain cholesteryl esters in TMZ-resistant cells Statin-based cholesterol inhibition fails to resensitize glioblastoma cells to temozolomide

cancer biology↗

bioRxiv2024

Evolving properties of biological materials captured via needle-based cavity expansion method

BackgroundThe mechanical properties of biological tissues change over time and with disease progression. Quantifying these mechanical properties can thus be instrumental for medical diagnosis and for evaluation of tissue viability for transplant. However, soft and biological materials are exceptionally challenging to mechanically characterize using conventional testing methods, which are hindered by limitations of sample size, fixturing capabilities, and sample preparation. ObjectiveWe hypothesize that Volume Controlled Cavity Expansion (VCCE) is well-suited to capture subtle mechanical differences in biological tissue. The objective of this work is therefore twofold: first, we seek to quantify how stiffness of liver and gelatin evolve with age. In achieving this understanding, we aim to demonstrate the precision of VCCE in measuring subtle changes in the mechanical properties of biological tissues. MethodsPerforming VCCE tests over 15 days in samples of gelatin and liver (porcine and bovine), we track the evolving pressure-volume response and deformation limits of the materials. ResultsIn both materials, we observed time-dependent variation of the stiffness and fracture thresholds. In gelatin VCCE repeatably captured stiffening over time, which was correlated with a higher fracture stress. This was in contrast to observations in bovine liver, where stiffening corresponded to a lower fracture stress. Porcine liver initially stiffened, then reversed this trend and relaxed. ConclusionThrough this work we show that liver and gelatin stiffen with age, and that this trend is measurable via VCCE. These results highlight the utility of VCCE and call attention to the need for a new class of mechanism based constitutive models that are capable of capturing variations in material over time with a minimal number of parameters.

bioengineering↗