Ceramides Increase Fatty Acid Utilization in Intestinal Progenitors to Enhance Stemness and Increase Tumor Risk

Liu, Ying; Chaurasia, Bhagirath; Rahman, Mohammed Mahidur; Kaddai, Vincent; Maschek, J. Alan; Berg, Jordan A.; Wilkerson, Joseph L.; Mahmassani, Ziad; Cox, James E.; Wei, Peng; Meikle, Peter J.; Atkinson, Donald L.; Wang, Liping; Poss, Annelise M; Playdon, Mary C.; Tippetts, Trevor S.; Mousa, Esraa; Nittayaboon, Kesara; Babu, Pon Velayutham Anandh; Drummond, Micah J.; Shayman, James A.; Hirabayashi, Yoshio; Holland, William L.; Rutter, Jared; Edgar, Bruce A.; Summers, Scott A.

doi:10.1053/j.gastro.2023.07.017

Cited by 18 publications

(5 citation statements)

References 47 publications

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“…Low FASM-risk patients get more satisfactory clinical benefits after immune checkpoint (PD-1/PD- L1) blockade therapies. Furthermore, the enhanced stemness of tumor cells caused by abnormal FAs metabolism reduces the survival time of patients and increases the possibility of cancer recurrence [ 60 , 61 ]. Consequently, CSC niches works by recruiting immunosuppressive cells, such as cancer-associated fibroblasts, Tregs and M2 macrophages to enhance their pro-tumor activity [ 62 ].…”

Section: Discussionmentioning

confidence: 99%

Identification of fatty acids synthesis and metabolism-related gene signature and prediction of prognostic model in hepatocellular carcinoma

Zhengdong,

Xiaoying,

Shuhui

et al. 2024

Cancer Cell Int

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Background Fatty acids synthesis and metabolism (FASM)-driven lipid mobilization is essential for energy production during nutrient shortages. However, the molecular characteristics, physiological function and clinical prognosis value of FASM-associated gene signatures in hepatocellular carcinoma (HCC) remain elusive. Methods The Gene Expression Omnibus database (GEO), the Cancer Genome Atlas (TCGA), and International Cancer Genome Consortium (ICGC) database were utilized to acquire transcriptome data and clinical information of HCC patients. The ConsensusClusterPlus was employed for unsupervised clustering. Subsequently, immune cell infiltration, stemness index and therapeutic response among distinct clusters were decoded. The tumor immune dysfunction and exclusion (TIDE) algorithm was utilized to anticipate the response of patients towards immunotherapy, and the genomics of drug sensitivity in cancer (GDSC) tool was employed to predict their response to antineoplastic medications. Least absolute shrinkage and selection operator (LASSO) regression analysis and protein–protein interaction (PPI) network were employed to construct prognostic model and identity hub gene. Single cell RNA sequencing (scRNA-seq) and CellChat were used to analyze cellular interactions. The hub gene of FASM effect on promoting tumor progression was confirmed through a series of functional experiments. Results Twenty-six FASM-related genes showed differential expression in HCC. Based on these FASM-related differential genes, two molecular subtypes were established, including Cluster1 and Cluster2 subtype. Compared with cluster2, Cluster1 subtype exhibited a worse prognosis, higher risk, higher immunosuppressive cells infiltrations, higher immune escape, higher cancer stemness and enhanced treatment-resistant. PPI network identified Acetyl-CoA carboxylase1 (ACACA) as central gene of FASM and predicted a poor prognosis. A strong interaction between cancer stem cells (CSCs) with high expression of ACACA and macrophages through CD74 molecule (CD74) and integrin subunit beta 1 (ITGB1) signaling was identified. Finally, increased ACACA expression was observed in HCC cells and patients, whereas depleted ACACA inhibited the stemness straits and drug resistance of HCC cells. Conclusions This study provides a resource for understanding FASM heterogeneity in HCC. Evaluating the FASM patterns can help predict the prognosis and provide new insights into treatment response in HCC patients.

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Section: Discussionmentioning

confidence: 99%

Identification of fatty acids synthesis and metabolism-related gene signature and prediction of prognostic model in hepatocellular carcinoma

Zhengdong,

Xiaoying,

Shuhui

et al. 2024

Cancer Cell Int

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“…Ceramides also promote progression of metabolic dysfunction-associated steatohepatitis (MASH), a well-established risk factor for HCC (Chaurasia et al, 2019). We have previously proposed that modest increases of ceramides, at levels that are insufficient to induce apoptosis, reprogram metabolism in cells in a manner that might be protumorigenic(Li et al, 2023). Two of our findings in this study provide additional evidence supporting a tumor-promoting role for ceramides in HCC.…”

Section: Discussionmentioning

confidence: 99%

Phospholipid isotope tracing reveals β-catenin-driven suppression of phosphatidylcholine metabolism in hepatocellular carcinoma

VanSant-Webb,

Low,

Kuramoto

et al. 2023

Preprint

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Activating mutations in the CTNNB1 gene encoding β-catenin are among the most frequently observed oncogenic alterations in hepatocellular carcinoma (HCC). HCC with CTNNB1 mutations show profound alterations in lipid metabolism including increases in fatty acid oxidation and transformation of the phospholipidome, but it is unclear how these changes arise and whether they contribute to the oncogenic program in HCC. We employed untargeted lipidomics and targeted isotope tracing to quantify phospholipid production fluxes in an inducible human liver cell line expressing mutant β-catenin, as well as in transgenic zebrafish with activated β-catenin-driven HCC. In both models, activated β-catenin expression was associated with large changes in the lipidome including conserved increases in acylcarnitines and ceramides and decreases in triglycerides. Lipid flux analysis in human cells revealed a large reduction in phosphatidylcholine (PC) production rates as assayed by choline tracer incorporation. We developed isotope tracing lipid flux analysis for zebrafish and observed similar reductions in phosphatidylcholine synthesis flux accomplished by sex-specific mechanisms. The integration of isotope tracing with lipid abundances highlights specific lipid class transformations downstream of β-catenin signaling in HCC and suggests future HCC-specific lipid metabolic targets.

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“…Deletion of SPT subunit, SPTLC2, inhibits ISC proliferation in mice. 77 Similarly, disruption of SPT homologue lace or the ceramide synthase homologue schlank in Drosophila recapitulates the phenotype. 77 Conversely, treating Sptlc2 ‐knockout organoids with a ceramide analogue, C 2 ‐ceramide, rescues ISC proliferation.…”

Section: Metabolic Control Of Isc Homeostasismentioning

confidence: 97%

“… 77 Similarly, disruption of SPT homologue lace or the ceramide synthase homologue schlank in Drosophila recapitulates the phenotype. 77 Conversely, treating Sptlc2 ‐knockout organoids with a ceramide analogue, C 2 ‐ceramide, rescues ISC proliferation. RNA‐seq analysis revealed that ceramide activates fatty acid‐binding protein 1 (FABP1) through PPARα, which enhances fatty acid utilisation and ISC proliferation.…”

Section: Metabolic Control Of Isc Homeostasismentioning

confidence: 97%

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Nutrient metabolism in regulating intestinal stem cell homeostasis

Shi,

Wang

2024

Cell Proliferation

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Intestinal stem cells (ISCs) are known for their remarkable proliferative capacity, making them one of the most active cell populations in the body. However, a high turnover rate of intestinal epithelium raises the likelihood of dysregulated homeostasis, which is known to cause various diseases, including cancer. Maintaining precise control over the homeostasis of ISCs is crucial to preserve the intestinal epithelium's integrity during homeostasis or stressed conditions. Recent research has indicated that nutrients and metabolic pathways can extensively modulate the fate of ISCs. This review will explore recent findings concerning the influence of various nutrients, including lipids, carbohydrates, and vitamin D, on the delicate balance between ISC proliferation and differentiation.

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Ceramides Increase Fatty Acid Utilization in Intestinal Progenitors to Enhance Stemness and Increase Tumor Risk

Cited by 18 publications

References 47 publications

Identification of fatty acids synthesis and metabolism-related gene signature and prediction of prognostic model in hepatocellular carcinoma

Identification of fatty acids synthesis and metabolism-related gene signature and prediction of prognostic model in hepatocellular carcinoma

Phospholipid isotope tracing reveals β-catenin-driven suppression of phosphatidylcholine metabolism in hepatocellular carcinoma

Nutrient metabolism in regulating intestinal stem cell homeostasis

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