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Cancer-Associated Fibroblasts Shape a High-Lactate Microenvironment to Drive Perineural Invasion in Pancreatic Cancer via Histone Lactylation

ABSTRACT: Cancer-Associated Fibroblasts Shape a High-Lactate Microenvironment to Drive Perineural Invasion in Pancreatic Cancer via Histone Lactylation

PROVIDER: PRJNA1229487 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	SRR32512389_1.fastq.gz	Fastqsanger.gz
	SRR32512389_2.fastq.gz	Fastqsanger.gz
	SRR32512390_1.fastq.gz	Fastqsanger.gz
	SRR32512390_2.fastq.gz	Fastqsanger.gz
	SRR32512391_1.fastq.gz	Fastqsanger.gz

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Cancer-Associated Fibroblasts Shape a High-Lactate Microenvironment to Drive Perineural Invasion in Pancreatic Cancer via Histone Lactylation

Project description:Perineural invasion (PNI) is a pivotal prognostic factor in pancreatic cancer, associated with aggressive tumor behavior and adverse patient outcomes. Despite its recognized clinical impact, the molecular mechanisms underlying PNI are not well understood. In this study, we isolated perineural invasion-associated cancer-associated fibroblasts (pCAFs), which demonstrated a markedly enhanced capacity to promote neural invasion in pancreatic cancer compared to non-perineural invasion-associated CAFs (npCAFs). Utilizing single-cell, high-throughput sequencing, and metabolomics, we identified a significant upregulation of glycolysis in pCAFs, fostering a high-lactate tumor microenvironment conducive to cancer progression. pCAFs-derived lactate is absorbed by tumor cells, facilitating histone H3K18 lactylation. This epigenetic modification activates the transcription of neural invasion-associated genes such as L1CAM and SLIT1, thereby driving PNI in pancreatic cancer. Further exploration of metabolic reprogramming in pCAFs revealed enhanced acetylation of the glycolytic enzyme GAPDH, correlated with increased enzymatic activity and glycolytic flux. Targeting of GAPDH and lactylation modifications significantly inhibits neural invasion in a KPC mouse model. Clinical data suggested that high levels of H3K18 lactylation correlate with severe PNI and poorer patient prognosis. Our findings provide critical insights into the role of pCAFs in the PNI of pancreatic cancer, highlighting glycolytic reprogramming and lactate-driven histone modifications as potential therapeutic targets for PDAC.

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Cancer-Associated Fibroblasts Shape a High-Lactate Microenvironment to Drive Perineural Invasion in Pancreatic Cancer via Histone Lactylation [RNA-seq]

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Lactylation-driven NSUN2-mediated RNA m5C modification promotes perineural invasion in pancreatic cancer [mRNA-seq]

Project description:Lactylation, a metabolic stress-induced modification, plays a pivotal role in regulating diverse biological processes. Its involvement in perineural invasion (PNI) of pancreatic ductal adenocarcinoma (PDAC), however, has not been clearly defined. Our study demonstrates that patients with severe PNI exhibit significantly elevated levels of global lactylation and lactate, correlating with poorer prognosis. We identified NSUN2, a methyltransferase, as a crucial mediator of lactylation-driven PNI. Inhibition of lactylation or NSUN2 markedly reduced the neural infiltration capabilities of tumor cells. Mechanistically, lactate accumulation leads to the lactylation of NSUN2 at lysine 692 (K692), subsequently inhibiting its ubiquitination and degradation. lactylation of NSUN2 mediated m5C modification on CDCP1 and STC11 mRNA, enhanced their mRNA stability. Consistently, analyses using a KPC mouse model demonstrated that the lactylation of NSUN2/CDCP1/STC11 axis enhanced PNI through m5C modification. Our findings reveal that lactylation-driven NSUN2-mediated RNA m5C modification plays a pivotal role in promoting PNI and suggest that targeting NSUN2 could offer a promising therapeutic strategy for PDAC.

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Lactylation-driven NSUN2-mediated RNA m5C modification promotes perineural invasion in pancreatic cancer [RIP-seq]

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Cancer-Associated Fibroblasts Shape a High-Lactate Microenvironment to Drive Perineural Invasion in Pancreatic Cancer via Histone Lactylation [RNA-seq]

Project description:Cancer-Associated Fibroblasts Shape a High-Lactate Microenvironment to Drive Perineural Invasion in Pancreatic Cancer via Histone Lactylation [RNA-seq]

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Lactate-mediated histone lactylation promotes melanoma angiogenesis

Project description:The pathogenesis of cancer is rather complicated and includes multiple aspects, with metabolic reprogramming and angiogenesis as the leading hallmark characteristics. Recent reports have unveiled that the glycolytic metabolite lactate could modify histone lactylation level to epigenetically regulate gene expressions and biological processes in cancer, while the role of lactate-mediated histone lactylation in tumor angiogenesis remains elusive. By taking advantage of melanoma as the model, we demonstrate that lactate-mediated histone lactylation promotes tumor angiogenesis via IL-33/ST2 axis.

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Project description:Lactylation-driven NSUN2-mediated RNA m5C modification promotes perineural invasion in pancreatic cancer [mRNA-seq]

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Project description:Hexokinase catalyzes the first committed step in glucose metabolism by phosphorylating glucose to produce glucose-6-phosphate. Highly glycolytic proliferating cells such as cancer cells take advantage of HK2 expression to accelerate glucose metabolism even in the presence of oxygen. This acceleration not only provides sufficient glycolytic intermediates to support the anabolic demands of the cells but also inevitably accompanies increased formation of metabolic end products such as lactate. Currently, the effect of lactate caused by HK2-mediated metabolic alteration is largely unknown. A recent study found that lactate plays a role in an epigenetic alteration known as histone lactylation. Here, using RNA-seq and CUT&Tag chromatin profiling, we study the effect of HK2 and lactate on gene expression via histone lactylation (H3K18la).

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