Targeting fatty acid metabolism in glioblastoma

Miska, Jason; Chandel, Navdeep S.

doi:10.1172/jci163448

Cited by 41 publications

(23 citation statements)

References 136 publications

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“…Our study raises several intriguing questions for future exploration: (1) Is the identified axis of p53 inactivation -astrocyte infiltration -FA metabolism relevant also to primary brain tumors? Glioblastomas commonly inactivate p53 (86), and have been recently shown to depend on FAS (49,(87)(88)(89)(90), suggesting that our findings may be relevant to primary brain tumors as well. ( 2) What is the exact molecular mechanism by which p53 regulates FA metabolism in the context of BCBM?…”

Section: Discussionmentioning

confidence: 75%

Inactivation of p53 drives breast cancer brain metastasis by altering fatty acid metabolism

Laue,

Pozzi,

Cohen-Sharir

et al. 2023

Preprint

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Brain metastasis (BM) is a dire prognosis across cancer types. It is largely unknown why some tumors metastasize to the brain whereas others do not. We analyzed genomic and transcriptional data from clinical samples of breast cancer BM (BCBM) and found that nearly all of them carried p53-inactivating genetic alterations through mutations, copy-number loss, or both. Importantly, p53 pathway activity was already perturbed in primary tumors giving rise to BCBM, often by loss of the entire 17p chromosome-arm. This association was recapitulated across other carcinomas. Experimentally, p53 knockout was sufficient to drastically increase BCBM formation and growthin vivo, providing a causal link between p53 inactivation and brain tropism. Mechanistically, p53-deficient BC cells exhibited altered lipid metabolism, particularly increased fatty acid (FA) synthesis and uptake, which are characteristic of brain-metastasizing cancer cells. FA metabolism was further enhanced by astrocytes in a p53-dependent manner, as astrocyte-conditioned medium increased FASN, SCD1, and CD36 expression and activity, and enhanced the survival, proliferation and migration of p53-deficient cancer cells. Consequently, these cells were more sensitive than p53-competent cells to FA synthesis inhibitors, in isogenic cell cultures, in BCBM-derived spheroids, and across dozens of BC cell lines. Lastly, a significant association was observed between p53 inactivation, astrocyte infiltration, and SCD1 expression in clinical human BCBM samples. In summary, our study identifies p53 inactivation as a driver of BCBM and potentially of BM in general; suggests a p53-dependent effect of astrocytes on BC cell behavior; and reveals FA metabolism as an underlying, therapeutically-targetable molecular mechanism.

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Section: Discussionmentioning

confidence: 75%

Inactivation of p53 drives breast cancer brain metastasis by altering fatty acid metabolism

Laue,

Pozzi,

Cohen-Sharir

et al. 2023

Preprint

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“…Lipid metabolism influences several processes that play a crucial role in the development and progression of GBM. Tumor-mediated reprogramming of these processes encompasses changes in import/export signaling pathways, lipid anabolism, catabolism (fatty acid oxidation), regulation of ferroptosis, and alteration in de novo lipid synthesis and signaling pathways that include lipogenesis and cholesterol synthesis and targeting these pathways may represent a potential therapeutic strategy to overcome GBM progression and disease recurrence [ 41 , 42 , 43 ]. Fatty acid metabolism has been shown to contribute to immune suppression in GBM.…”

Section: Discussionmentioning

confidence: 99%

Spatially Resolved Microglia/Macrophages in Recurrent Glioblastomas Overexpress Fatty Acid Metabolism and Phagocytic Genes

Mistry,

Daneshmand,

Seo

et al. 2024

Current Oncology

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Background: Glioblastoma (GBM) tumors are rich in tumor-associated microglia/macrophages. Changes associated with treatment in this specific cell population are poorly understood. Therefore, we studied changes in gene expression of tumor-associated microglia/macrophages (Iba1+) cells in de novo versus recurrent GBMs. Methods: NanoString GeoMx® Digital Spatial Transcriptomic Profiling of microglia/macrophages (Iba1+) and glial cells (Gfap+) cells identified on tumor sections was performed on paired de novo and recurrent samples obtained from three IDH-wildtype GBM patients. The impact of differentially expressed genes on patient survival was evaluated using publicly available data. Results: Unsupervised analyses of the NanoString GeoMx® Digital Spatial Profiling data revealed clustering based on the transcriptomic data from Iba1+ and Gfap+ cells. As expected, conventional differential gene expression and enrichment analyses revealed upregulation of immune-function-related genes in Iba1+ cells compared to Gfap+ cells. A focused differential gene expression analysis revealed upregulation of phagocytosis and fatty acid/lipid metabolism genes in Iba1+ cells in recurrent GBM samples compared to de novo GBM samples. Importantly, of these genes, the lipid metabolism gene PLD3 consistently correlated with survival in multiple different publicly available datasets. Conclusion: Tumor-associated microglia/macrophages in recurrent GBM overexpress genes involved in fatty acid/lipid metabolism. Further investigation is needed to fully delineate the role of PLD phospholipases in GBM progression.

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“…Ferroptosis, a new type of programmed cell death, has been proven to be induced by the overloading of cellular iron and ROS 36 . During the past decades of research, the regulatory factors of ferroptosis have been proposed to participate in the gliomagenesis and anti‐tumor responses 37 . In glioma cells U251 and U87, overexpression of NEDD4L significantly reinforced the cytotoxic effects induced by the natural compound paeoniflorin (PF), accompanied by inhibition of cell viability and induction of ferroptosis 38 .…”

Section: Discussionmentioning

confidence: 99%

FHOD1 is upregulated in glioma cells and attenuates ferroptosis of glioma cells by targeting HSPB1 signaling

Zhang

Feng

et al. 2023

CNS Neurosci Ther

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BackgroundAs a new type of regulatory cell death, ferroptosis has been proven to be involved in cancer pathogenesis and therapeutic response. However, the detailed roles of ferroptosis or ferroptosis‐associated genes in glioma remain to be clarified.MethodsHere, we performed the TMT/iTRAQ‐Based Quantitative Proteomic Approach to identify the differentially expressed proteins between glioma specimens and adjacent tissues. Kaplan–Meier survival was used to estimate the survival values. We also explored the regulatory roles of abnormally expressed formin homology 2 domain‐containing protein 1 (FHOD1) in glioma ferroptosis sensitivity.ResultsIn our study, FHOD1 was identified to be the most significantly upregulated protein in glioma tissues. Multiple glioma datasets revealed that the glioma patients with low FHOD1 expression displayed favorable survival time. Functional analysis proved that the knockdown of FHOD1 inhibited cell growth and improved the cellular sensitivity to ferroptosis in glioma cells T98G and U251. Mechanically, we found the up‐regulation and hypomethylation of HSPB1, a negative regulator of ferroptosis, in glioma tissues. FHOD1 knockdown could enhance the ferroptosis sensitivity of glioma cells via up‐regulating the methylated heat‐shock protein B (HSPB1). Overexpression of HSPB1 significantly reversed FHOD1 knockdown‐mediated ferroptosis.ConclusionsIn summary, this study demonstrated that the FHOD1‐HSPB1 axis exerts marked regulatory effects on ferroptosis, and might affect the prognosis and therapeutic response in glioma.

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Targeting fatty acid metabolism in glioblastoma

Cited by 41 publications

References 136 publications

Inactivation of p53 drives breast cancer brain metastasis by altering fatty acid metabolism

Inactivation of p53 drives breast cancer brain metastasis by altering fatty acid metabolism

Spatially Resolved Microglia/Macrophages in Recurrent Glioblastomas Overexpress Fatty Acid Metabolism and Phagocytic Genes

FHOD1 is upregulated in glioma cells and attenuates ferroptosis of glioma cells by targeting HSPB1 signaling

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