Summary of Study ST004262
This data is available at the NIH Common Fund's National Metabolomics Data Repository (NMDR) website, the Metabolomics Workbench, https://www.metabolomicsworkbench.org, where it has been assigned Project ID PR002689. The data can be accessed directly via it's Project DOI: 10.21228/M82R9H This work is supported by NIH grant, U2C- DK119886. See: https://www.metabolomicsworkbench.org/about/howtocite.php
| Study ID | ST004262 |
| Study Title | The lipidome of drug-resistant glioblastoma persister cells. |
| Study Summary | This study aimed to determine mechanisms through which glioblastoma stem cells acquire a drug-resistant phenotype. A small proportion of glioblastoma stem cells survive chemotherapy and radiotherapy, creating a drug-resistant persister cell population that resumes proliferation after the cessation of drug treatment. The specific experiment profiled the lipidome of glioblastoma stem cells that survive treatment with the anti-microtubule agent CMPD1. Glioblastoma stem cell line RKI1 was treated for 14 days with 25 micromolar CMPD1 to generate drug-resistant persister cells, replacing the cell culture medium every 3 days (n = 3). At day 14 of treatment, the CMPD1-treated cells were collected for lipid extraction and lipidomic analysis. The drug-resistant persister cells were compared to control cells grown in RKI1 growth medium and collected prior to drug-treatment (n = 3). The drug-resistant persister cells displayed significantly decreased levels of ceramide and cholesterol, and increased sphingomyelin and diacylgylcerol, indicative of membrane remodelling that may allow the cells to survive chemotherapy. Further investigation indicated that the reduced cholesterol content provides a point of metabolic vulnerability to eliminate the drug resistant persister cells. |
| Institute | University of Sydney |
| Department | School of Medical Sciences |
| Last Name | Don |
| First Name | Anthony |
| Address | Office 3210, D17 Charles Perkins Centre, Camperdown, NSW, 2006 |
| anthony.don@sydney.edu.au | |
| Phone | +612 8627 5578 |
| Submit Date | 2025-09-29 |
| Num Groups | 2 |
| Total Subjects | 6 |
| Study Comments | Control and drug-treated RKI1 glioblastoma cells |
| Publications | Histone methyltransferase PRDM9 promotes survival of drug-tolerant persister cells in glioblastoma |
| Raw Data Available | Yes |
| Raw Data File Type(s) | mzML |
| Analysis Type Detail | LC-MS |
| Release Date | 2025-10-10 |
| Release Version | 1 |
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Project:
| Project ID: | PR002689 |
| Project DOI: | doi: 10.21228/M82R9H |
| Project Title: | Histone methyltransferase PRDM9 promotes survival of drug-tolerant persister cells in glioblastoma |
| Project Summary: | Chemotherapy often kills a large fraction of cancer cells but leaves behind a small population of drug tolerant persister cells. These persister cells survive drug treatments through reversible, non-genetic mechanisms and cause tumour recurrence upon cessation of therapy. Here, we report a drug tolerance mechanism regulated by the germ-cell-specific H3K4 methyltransferase PRDM9. Through histone proteomic, transcriptomic, lipidomic, and ChIP-sequencing studies combined with CRISPR knockout and phenotypic drug screen, we identified that chemotherapy-induced PRDM9 upregulation promotes metabolic rewiring in glioblastoma stem cells, leading to chemotherapy tolerance. Mechanistically, PRDM9-dependent H3K4me3 at cholesterol biosynthesis genes enhances cholesterol biosynthesis, which persister cells rely on to maintain homeostasis under chemotherapy induced oxidative stress and lipid peroxidation. PRDM9 inhibition, combined with chemotherapy, resulted in strong anti-cancer efficacy in preclinical glioblastoma models, significantly enhancing the magnitude and duration of the antitumor response by eliminating persisters. These findings demonstrate a previously unknown role of PRDM9 in promoting metabolic reprogramming that enables the survival of drug-tolerant persister cells. |
| Institute: | The University of Sydney |
| Department: | School of Medical Sciences |
| Last Name: | Don |
| First Name: | Anthony |
| Address: | Office 3210, D17 Charles Perkins Centre, Camperdown, NSW, 2006, Australia |
| Email: | anthony.don@sydney.edu.au |
| Phone: | +612 8627 5578 |
| Publications: | Histone methyltransferase PRDM9 promotes survival of drug-tolerant persister cells in glioblastoma |
