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Porphyrin overdrive rewires cancer cell metabolism

ABSTRACT: Porphyrin overdrive rewires cancer cell metabolism

PROVIDER: PRJNA1099386 | ENA |

REPOSITORIES: ENA

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Porphyrin overdrive rewires cancer cell metabolism

Project description:All cancer cells reprogram metabolism to support aberrant growth. Here, we report that cancer cells employ and depend on imbalanced and dynamic heme metabolic pathways, to accumulate heme intermediates, i.e., porphyrins. We coined this essential metabolic rewiring ‘porphyrin overdrive’ and determined that it is cancer-essential and cancer-specific. Among the major drivers are genes encoding mid-step enzymes governing the production of heme intermediates. CRISPR/Cas9 editing to engineer leukemia cell lines with impaired heme biosynthetic steps confirmed our whole genomic data analyses that porphyrin overdrive is linked to oncogenic states and cellular differentiation. While porphyrin overdrive is absent in differentiated cells or somatic stem cells, it is present in patient-derived tumor progenitor cells, demonstrated by single cell RNAseq, and in early embryogenesis. In conclusion, we identified a dependence of cancer cells on non-homeostatic heme metabolism, and we targeted this cancer metabolic vulnerability with a novel “bait-and-kill” strategy to eradicate malignant cells.

2024-04-17 | GSE263829 | GEO

Estrogen receptor and mTOR signaling rewires cancer metabolism in obesity-associated breast cancer

Project description:Estrogen receptor and mTOR signaling rewires cancer metabolism in obesity-associated breast cancer

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Lactate rewires lipid metabolism and sustains a metabolic-epigenetic interplay in prostate cancer

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Estrogen Receptor α (ERα)-mTOR signaling crosstalk rewires cancer cell metabolism providing a mechanism underlying obesity-associated postmenopausal breast cancer

Project description:Estrogen Receptor α (ERα)-mTOR signaling crosstalk rewires cancer cell metabolism providing a mechanism underlying obesity-associated postmenopausal breast cancer

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Histone variant macroH2A1 rewires carbohydrate and lipid metabolism of hepatocellular carcinoma cells towards cancer stem cells

Project description:Histone variant macroH2A1 rewires carbohydrate and lipid metabolism of hepatocellular carcinoma cells towards cancer stem cells

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Where Does the Heme Go? Unraveling Heme and Porphyrin Metabolism in Healthy and Oncogenic Human Livers

Project description:The liver, a pivotal organ in human metabolism, serves as a primary site for heme biosynthesis, critical for detoxification and drug metabolism. Maintaining precise control over heme production is paramount in healthy livers to meet high metabolic demands while averting potential toxicity from intermediate metabolites, notably protoporphyrin IX. Intriguingly, our recent research uncovers a disrupted heme biosynthesis process termed 'Porphyrin Overdrive' in cancers, fostering the accumulation of heme intermediates, potentially bolstering tumor survival. Here, we investigate heme and porphyrin metabolism in both healthy and oncogenic human livers, utilizing primary human liver transcriptomics and single-cell RNA sequencing (scRNAseq). Our investigations unveil robust gene expression patterns in heme biosynthesis in healthy livers, supporting electron transport chain (ETC) and cytochrome P450 function, devoid of intermediate accumulation. Conversely, liver cancers exhibit impaired heme biosynthesis and massive downregulation of cytochrome P450 expression. Notably, despite diminished drug metabolism, heme supply to the ETC remains largely unaltered or even elevated with cancer progression, suggesting a metabolic priority shift. Liver cancers selectively accumulate intermediates, absent in normal tissues, implicating their role in disease advancement as inferred by expression. Furthermore, our findings establish a link between diminished drug metabolism, augmented ETC function, porphyrin accumulation, and inferior overall survival in aggressive cancers, indicating potential targets for clinical therapy development.

2024-09-13 | GSE268462 | GEO

Gut microbiota rewires host mRNA m6A epitranscriptomic landscape via bile acid metabolism

Project description:Gut microbiota rewires host mRNA m6A epitranscriptomic landscape via bile acid metabolism

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Activation of the integrated stress response rewires cardiac metabolism in Barth syndrome

Project description:Activation of the integrated stress response rewires cardiac metabolism in Barth syndrome

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Gut microbiota dysbiosis rewires host mRNA m6A epitranscriptomic landscape via bile acid metabolism

Project description:Gut microbiota dysbiosis rewires host mRNA m6A epitranscriptomic landscape via bile acid metabolism

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Estrogen receptor and mTOR signaling rewires cancer metabolism in obesity-associated breast cancer

Project description:Obesity is a risk factor for postmenopausal ERα (+) breast cancer. Molecular mechanisms activated by the factors from serum that contribute to this risk and how these mechanisms affect ERα signaling are yet to be elucidated. To identify such mechanisms, we performed whole metabolite and protein profiling in serum samples, which enabled us to focus on factors that were differentially present in serum from cancer-free vs. breast cancer susceptible and obese vs. non-obese post-menopausal women. These studies combined with in vitro assays identified free fatty acids (FFAs), as serum factors that correlate with increased proliferation and aggressiveness in ERα(+) breast cancer cells by. FFAs activated both ERα and mTOR pathways and rewired metabolism in breast cancer cells. Pathway preferential estrogen-1 (PaPE-1), which target ERα and mTOR signaling, was able to block changes induced by FFAs. In fact, PaPEs were more effective in the presence of FFAs, suggesting a role for obesity-associated gene and metabolic rewiring in providing new targetable vulnerabilities for ERα-(+) breast cancer in postmenopausal women. Our findings provide a basis for preventing or inhibiting obesity-associated breast cancer by using PaPEs that would reverse these newly appreciated metabolic properties of breast tumors in obese postmenopausal women.

2019-05-11 | GSE114372 | GEO

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