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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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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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Hexokinase 2 and lactate mediated gene expression via histone H3 lysine 18 lactylation (CHO RNA-Seq)

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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