Burman, R. | bioRxiv Science

bioRxiv2025

SLFN11 Loss-Induced Chemoresistance is Associated with Overexpression of Glycerophospholipid Biosynthesis in Ewing Sarcoma.

Ewing sarcoma (EWS) is an aggressive cancer in adolescents and young adults with frequent relapse rates and poor outcomes in recurrent or metastatic cases. Schlafen family member 11 (SLFN11) gene is associated with the sensitivity to DNA-damaging agents (DDAs). The knockout of SLFN11 is associated with acquired chemoresistance in both cell lines and preclinical models. Here, we aimed to elucidate the metabolic underpinnings of SLFN11-loss associated chemoresistance in patient derived cell lines of EWS. Our integrated transcriptomic and metabolomic analyses revealed downregulation of mitochondrial glycerol-3-phosphate dehydrogenase 2 (GPD2) gene, which was accompanied by the upregulation of glycerophospholipid (GPL) biosynthesis pathway. Further, therapeutic targeting of lipid synthesis with the glycerol-3-phosphate acyltransferase 1 (GPAT1) inhibitor (FSG67) enhanced the efficacy of the DDA (SN-38) in SLFN11-/- cells. These findings indicate that SLFN11 loss-mediated chemoresistance can be targeted by blocking GPL biosynthesis in addition to DDA administration.

cancer biology↗

bioRxiv2025

Enhanced Temporal-Resolution CEST Imaging method for reliable mapping of muscle OXPHOS

PurposeTo develop and validate a novel chemical exchange saturation transfer (CEST) MRI method to map skeletal muscle OXPHOS (Oxidative Phosphorylation CEST or OXCEST). Theory and MethodsOur proposed OXCEST method acquires creatine (Cr)-weighted CEST maps by applying RF saturation (B1) at only two frequency offsets: +1.8 ppm (targeting the Cr amine resonance) and -1.8 ppm (to calculate MTRasym at 1.8 ppm). The pre-exercise MTRasym is modeled as a second-order polynomial function (f) of B0. Next, the post-exercise alteration in MTRasym is hypothesized to be affected by both an exercise-induced increase in Cr and changes in B0 inhomogeneity. By inputting post-exercise B0 values into f, the change in MTRasym due to B0 variation alone was estimated. Thus, the Cr-related post-exercise MTRasym could be isolated and quantified. OXCEST and 31P-MRS were performed in seven subjects across two sessions to compare the OXCEST-derived Cr recovery time constant (TCr) with the ground-truth phosphocreatine recovery time constant (TPCr). ResultsA second-order polynomial function f could reliably describe the relationship between pre-exercise MTRasym and B0 (R2=0.87{+/-}0.07 in the lateral gastrocnemius (LG); R2=0.98{+/-}0.01 in the medial gastrocnemius (MG); R2=0.96{+/-}0.03 in the soleus). The mean pre-exercise MTRasym was approximately 6-7% for all muscle groups. Following exercise, MTRasym increased by 11.4{+/-}4.5% in LG and 8{+/-}2.4% in MG, and showed mono-exponential recovery (R2>0.97). The combined TCr of LG and MG was found to be significantly correlated with TPCr (R{superscript 2}=0.83, p=0.005). ConclusionOXCEST enables reliable assessment of post-exercise Cr recovery and demonstrated strong agreement with 31P-MRS.

bioengineering↗