Rewired lipid metabolism as an actionable vulnerability of aggressive colorectal carcinoma

Capece, Daria; Franzoso, Guido

doi:10.1080/23723556.2021.2024051

Cited by 5 publications

(7 citation statements)

References 18 publications

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“…Consistent with this idea, treatment with CES1 inhibitors effectively killed human CRC cells upon glucose limitation and markedly impaired CRC growth without apparent adverse effects in mouse allograft and xenograft models [ 258 , 259 , 260 ]. Collectively, these results identify CES1 as a promising therapeutic target, given its contextual specificity for energy stress conditions, correlation with poor clinical outcomes in obese CRC patients, and clear stratification with MSS/non-hypermutated CMS4 and CMS2 tumors, which do not respond to immunotherapy [ 258 , 259 , 260 ]. Accordingly, genetic CES1 deletion appears to be tolerated in vivo, since CES1 knockout mice are viable, lean, and die of old age [ 261 ].…”

Section: Therapeutic Targeting Of the Nf-κb Pathway In Cancermentioning

confidence: 89%

“…Consistently, the pharmacological co-inhibition of IKKβ and glutamine metabolism resulted in the synergistic killing of cancer cells, both in vitro and in vivo [ 257 ]. Recently, CES1 has been identified as an essential NF-κB-regulated lipase linking obesity-associated inflammation with metabolic adaptation to energy stress in aggressive CRC [ 258 , 259 , 260 ]. CES1 expression was upregulated in consensus molecular subtypes (CMS)4 and CMS2 tumors and correlated with worse clinical outcomes in overweight CRC patients [ 258 , 259 , 260 ], suggesting a role for CES1 in the pathogenesis of CRC.…”

Section: Therapeutic Targeting Of the Nf-κb Pathway In Cancermentioning

confidence: 99%

“…Recently, CES1 has been identified as an essential NF-κB-regulated lipase linking obesity-associated inflammation with metabolic adaptation to energy stress in aggressive CRC [ 258 , 259 , 260 ]. CES1 expression was upregulated in consensus molecular subtypes (CMS)4 and CMS2 tumors and correlated with worse clinical outcomes in overweight CRC patients [ 258 , 259 , 260 ], suggesting a role for CES1 in the pathogenesis of CRC. Consistent with this idea, treatment with CES1 inhibitors effectively killed human CRC cells upon glucose limitation and markedly impaired CRC growth without apparent adverse effects in mouse allograft and xenograft models [ 258 , 259 , 260 ].…”

Section: Therapeutic Targeting Of the Nf-κb Pathway In Cancermentioning

confidence: 99%

“…CES1 expression was upregulated in consensus molecular subtypes (CMS)4 and CMS2 tumors and correlated with worse clinical outcomes in overweight CRC patients [ 258 , 259 , 260 ], suggesting a role for CES1 in the pathogenesis of CRC. Consistent with this idea, treatment with CES1 inhibitors effectively killed human CRC cells upon glucose limitation and markedly impaired CRC growth without apparent adverse effects in mouse allograft and xenograft models [ 258 , 259 , 260 ]. Collectively, these results identify CES1 as a promising therapeutic target, given its contextual specificity for energy stress conditions, correlation with poor clinical outcomes in obese CRC patients, and clear stratification with MSS/non-hypermutated CMS4 and CMS2 tumors, which do not respond to immunotherapy [ 258 , 259 , 260 ].…”

Section: Therapeutic Targeting Of the Nf-κb Pathway In Cancermentioning

confidence: 99%

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The NF-κB Pharmacopeia: Novel Strategies to Subdue an Intractable Target

et al. 2022

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NF-κB transcription factors are major drivers of tumor initiation and progression. NF-κB signaling is constitutively activated by genetic alterations or environmental signals in many human cancers, where it contributes to almost all hallmarks of malignancy, including sustained proliferation, cell death resistance, tumor-promoting inflammation, metabolic reprogramming, tissue invasion, angiogenesis, and metastasis. As such, the NF-κB pathway is an attractive therapeutic target in a broad range of human cancers, as well as in numerous non-malignant diseases. Currently, however, there is no clinically useful NF-κB inhibitor to treat oncological patients, owing to the preclusive, on-target toxicities of systemic NF-κB blockade. In this review, we discuss the principal and most promising strategies being developed to circumvent the inherent limitations of conventional IκB kinase (IKK)/NF-κB-targeting drugs, focusing on new molecules that target upstream regulators or downstream effectors of oncogenic NF-κB signaling, as well as agents targeting individual NF-κB subunits.

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Section: Therapeutic Targeting Of the Nf-κb Pathway In Cancermentioning

confidence: 89%

Section: Therapeutic Targeting Of the Nf-κb Pathway In Cancermentioning

confidence: 99%

Section: Therapeutic Targeting Of the Nf-κb Pathway In Cancermentioning

confidence: 99%

Section: Therapeutic Targeting Of the Nf-κb Pathway In Cancermentioning

confidence: 99%

See 2 more Smart Citations

The NF-κB Pharmacopeia: Novel Strategies to Subdue an Intractable Target

et al. 2022

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“…Dysregulated lipid metabolism has been similarly linked to EMT in cancer; metastatic cells display increased lipolysis, which releases endogenous free fatty acids to generate the reduced form of NADPH through fatty acid oxidation (FAO) [ 54 ]. FAO confers a survival advantage for tumor cells by maintaining sufficient energy generation and redox homeostasis, as well as providing a source of lipids for membrane biogenesis [ 55 ]. It is possible that TGFβ2-treated RPE overutilize and deplete fatty acid supplies to enable increased FAO.…”

Section: Discussionmentioning

confidence: 99%

Divergent Metabolomic Signatures of TGFβ2 and TNFα in the Induction of Retinal Epithelial-Mesenchymal Transition

Saint‐Geniez

Kim

et al. 2023

Metabolites

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Epithelial-mesenchymal transition (EMT) is a dedifferentiation program in which polarized, differentiated epithelial cells lose their cell-cell adhesions and transform into matrix-producing mesenchymal cells. EMT of retinal pigment epithelial (RPE) cells plays a crucial role in many retinal diseases, including age-related macular degeneration, proliferative vitreoretinopathy, and diabetic retinopathy. This dynamic process requires complex metabolic reprogramming to accommodate the demands of this dramatic cellular transformation. Both transforming growth factor-beta 2 (TGFβ2) and tumor necrosis factor-alpha (TNFα) have the capacity to induce EMT in RPE cells; however, little is known about their impact on the RPE metabolome. Untargeted metabolomics using high-resolution mass spectrometry was performed to reveal the metabolomic signatures of cellular and secreted metabolites of primary human fetal RPE cells treated with either TGFβ2 or TNFα for 5 days. A total of 638 metabolites were detected in both samples; 188 were annotated as primary metabolites. Metabolomics profiling showed distinct metabolomic signatures associated with TGFβ2 and TNFα treatment. Enrichment pathway network analysis revealed alterations in the pentose phosphate pathway, galactose metabolism, nucleotide and pyrimidine metabolism, purine metabolism, and arginine and proline metabolism in TNFα-treated cells compared to untreated control cells, whereas TGFβ2 treatment induced perturbations in fatty acid biosynthesis metabolism, the linoleic acid pathway, and the Notch signaling pathway. These results provide a broad metabolic understanding of the bioenergetic rewiring processes governing TGFβ2- and TNFα-dependent induction of EMT. Elucidating the contributions of TGFβ2 and TNFα and their mechanistic differences in promoting EMT of RPE will enable the identification of novel biomarkers for diagnosis, management, and tailored drug development for retinal fibrotic diseases.

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Proteogenomic and observational evidence implicate ANGPTL4 as a potential therapeutic target for colorectal cancer prevention

Yarmolinsky,

Lee,

Lau

et al. 2024

Preprint

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Background: Preclinical, observational, and genetic epidemiological evidence implicate circulating lipids in cancer development. The role of approved and emerging lipid-perturbing medications in cancer risk is unclear. Patients and methods: We employed cis-Mendelian randomization (MR) and colocalisation to evaluate the role of 5 lipid-perturbing drug targets (ANGPTL3, ANGPTL4, APOC3, CETP, PCSK9) in risk of 5 cancers (breast, colorectal, head and neck, ovarian, prostate) in up to 319,661 cases and 348,078 controls. We further triangulated findings using direct measures of pre-diagnostic protein targets in case-cohort analyses in the European Prospective Investigation into cancer and Nutrition (EPIC). To gain mechanistic insight into the role of ANGPTL4 in carcinogenesis, we examined the impact of the ANGPTL4 p.E40K loss-of-function variant on differential gene expression in normal colon tissue in the BarcUVa-Seq project. Finally, we evaluated the association of ANGPTL4 gene expression in colon tumour tissue with all-cause mortality in The Cancer Genome Atlas (TCGA). Results: In analysis of 78,473 cases and 107,143 controls, genetically-proxied circulating ANGPTL4 inhibition was associated with a reduced risk of colorectal cancer (OR per SD decrease: 0.76, 95% CI 0.66-0.89, P = 5.52 x 10-4, colocalisation posterior probability = 0.83). This association was replicated in the EPIC cohort using pre-diagnostic circulating ANGPTL4 concentrations in 977 incident colorectal cancer cases and 4,080 sub-cohort members (HR per log10 decrease: 0.92, 95% CI 0.85-0.99, P = 0.02). In gene set enrichment analysis of differential gene expression in 445 normal colon tissue samples, ANGPTL4 loss-of-function was associated with down-regulation of several biological pathways implicated in cancer (FDR P < 0.05), including those involved in cellular proliferation, epithelial-to-mesenchymal transition, and bile acid metabolism. In analysis of 465 colon cancer patients, lower ANGPTL4 expression in tumour tissue was associated with reduced risk of all-cause mortality (HR per log2 decrease: 0.85, 95% CI 0.73-0.99; P = 0.04). There was little evidence of association of genetically-proxied inhibition of ANGPTL4 or other lipid targets with the other cancer outcomes evaluated. Conclusion: Our integrative proteogenomic and observational analyses suggest a protective role of lower circulating ANGPTL4 concentrations in colorectal cancer risk. These findings support further evaluation of ANGPTL4, an emerging drug target for hypertriglyceridemia, as a potential therapeutic target for colorectal cancer prevention.

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Rewired lipid metabolism as an actionable vulnerability of aggressive colorectal carcinoma

Cited by 5 publications

References 18 publications

The NF-κB Pharmacopeia: Novel Strategies to Subdue an Intractable Target

The NF-κB Pharmacopeia: Novel Strategies to Subdue an Intractable Target

Divergent Metabolomic Signatures of TGFβ2 and TNFα in the Induction of Retinal Epithelial-Mesenchymal Transition

Proteogenomic and observational evidence implicate ANGPTL4 as a potential therapeutic target for colorectal cancer prevention

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