Dataset Information

Intrinsic metabolic dependencies of glioblastoma tumor initiating cells dictate the sensitivity to LSD1-directed therapy

ABSTRACT: Lysine-specific histone demethylase 1A (LSD1) is an epigenetic regulator involved in several biological processes, including metabolic pathways. We established the therapeutic benefit of its pharmacological inhibition in glioblastoma (GBM) using DDP_38003 (LSD1i), which selectively targets tumor-initiating cells (TICs) by hampering their adaptability to stress. Here, we demonstrate that LSD1i is a stress-inducing agent activating the integrated stress response by itself and triggering rearrangements of mitochondria which impact TICs oxidative metabolism.

INSTRUMENT(S):

ORGANISM(S): Homo Sapiens (human)

DISEASE(S): Brain Cancer

SUBMITTER: Roberta Noberini

LAB HEAD: Tiziana Bonaldi

PROVIDER: PXD053770 | Pride | 2026-05-25

REPOSITORIES: Pride

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			Action	DRS
	Marotta.zip	Other
	QEPLIS_210202_RN_Brunella_1.raw	Raw
	QEPLIS_210202_RN_Brunella_10.raw	Raw
	QEPLIS_210202_RN_Brunella_11.raw	Raw
	QEPLIS_210202_RN_Brunella_12.raw	Raw

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Publications

Metabolic traits shape responses to LSD1-directed therapy in glioblastoma tumor-initiating cells.

Marotta Giulia G Osti Daniela D Zaccheroni Elena E Costanza Brunella B Faletti Stefania S Marinaro Adriana A Richichi Cristina C Mesa Deborah D Rodighiero Simona S Soriani Chiara C Migliaccio Enrica E Ruscitto Federica F Priami Chiara C Sigismund Sara S Manetti Francesco F Polli Dario D Beznusenko Galina V GV Rusu Mara-Camelia MC Favero Francesco F Corà Davide D Silvestris Domenico A DA Gallo Angela A Gambino Valentina V Alfieri Fabio F Gandini Sara S Schmitt Matthias J MJ Gargiulo Gaetano G Noberini Roberta R Bonaldi Tiziana T Pelicci Giuliana G

Science advances 20250523 21

Lysine-specific histone demethylase 1A (LSD1) is an epigenetic regulator involved in various biological processes, including metabolic pathways. We demonstrated the therapeutic potential of its pharmacological inhibition in glioblastoma using DDP_38003 (LSD1i), which selectively targets tumor-initiating cells (TICs) by hampering their adaptability to stress. Through biological, metabolic, and omic approaches, we now show that LSD1i acts as an endoplasmic reticulum (ER) stressor, activating the i ...[more]

PMID: 40408499

Similar Datasets

Project description:Glioblastomas (GBM) are poorly differentiated astrocytic tumors arising in the Central Nervous System (CNS), which despite aggressive treatments are still characterized by a fatal outcome. Several studies have shown the existence of a subpopulation of cells within glioma tumors displaying cancer stem cells properties. As the term âtumor initiating cellsâ (TICs) is frequentely used to describe cells as these with cancer stem cells capacity. Because TICs promotes the tumor chemo- and radio-resistance and angiogenesis it is conceivable that finding a mean to kill these cells would lead to a better therapy for GBM. The NOTCH gene has an important role during the CNS development, in the maintenance of dividing cells in promoting neural lineage entry of Embryonic Stem Cells and the differentiation of astroglia from the rat adult hippocampus-derived multipotent progenitors. The activation of the NOTCH signaling requires the proteolytic processing of this type I integral membrane protein by a two step process catalyzed first by a metalloprotease and then by the gamma-secretase. An increased activation of the NOTCH signaling has been implicated in several tumors types. Recently some studies showed that this pathway induces the survival/proliferation in GBM and glioma cells, and the expression of stem cell properties in glioma cells. Accordingly to these findings, the inhibition of this pathway leads to depletion of stem-like cells and blocks the engraftment in embryonal brain tumors. Furthermore, enhanced NOTCH signaling may lead to one of the tumor resistance mechanisms deployed by GBM. Targeting the NOTCH pathway specifically in GBM TICs appears therefore as a rational approach for exploring novel and hopefully more effective therapeutic strategies for the management of this malignancy. Several molecular tools are available for targeting the Notch pathway such as specific siRNAs, shRNAs or drugs such as gamma-secretase inhibitors. Among these tools, the latter are small peptides/molecules able to inhibit the gamma-secretase by distinct mechanisms. In this study we used two drugs known as gamma-secretase inhibitors, to investigate by gene expression profiling, their ability to interfere specifically with the proliferative properties of GBM TICs previously obtained in our laboratory. Our data show that one of these two drugs, LLNle, is effective in killing these cells in vitro by activating protein catabolic process mediated by the proteasome, suggesting that preclinical studies should definitely be carried on to evaluate whether LLNle is able to significantly improve the survival in hybrid human GBM-animal models. Gamma-secretase inhibitors have been proposed as drugs able to kill cancer cells by targeting the NOTCH pathway. In this study we employed two of such inhibitors, namely the z-Leu-leu-Nle-CHO (LLNle) and N-[N-(3,5-difluorophenacetyl)-L-alanyl]-S-phenylglycine t-butyl ester (DAPT), to verify whether they were effective in vitro in the killing of human GBM tumor initiating cells (TICs). We first established that of the two drugs only LLNle reduces the viability of GBM TICs obtained from three different patients in the low micromolar range. Cells were treated with 7.5 Î¼M LLNle or DAPT or vehicle alone (DMSO 0.1%) and kept in a humidified 5% CO2 atmosphere at 37Â°C for the indicated time period (24 or 48 hours). To establish which cellular processes are activated in GBM TICs by LLNle we generated and analyzed the gene expression profile after treatment with this compound and with DAPT and DMSO (vehicle). Our data show that LLNle induces upregulation of genes coding for proteasome subunits and subsequently mitotic arrest in these cells by repressing genes required for DNA synthesis and mitotic progression and by activation of genes acting as mitotic inhibitors. Our data are consistent with proteasome inhibition by LLNle, subsequent upregulation of proteasome activity and subsequent unleash of the apoptotic process in GBM TICs.