Dataset Information

PYGL-mediated glucose metabolism reprogramming promotes EMT phenotype and metastasis of pancreatic cancer.

ABSTRACT: Epithelial-mesenchymal transition (EMT) is closely associated with tumor invasion and metastasis. However, key regulators of EMT in pancreatic ductal adenocarcinoma (PDAC) need to be further studied. Bioinformatics analyses of pancreatic cancer public datasets showed that glycogen phosphorylase L (PYGL) expression is elevated in quasimesenchymal PDAC (QM-PDAC) and positively associated with EMT. In vitro cellular experiments further confirm PYGL as a crucial EMT regulator in PDAC cells. Functionally, PYGL overexpression promotes cell migration and invasion in vitro and facilitates liver metastasis in vivo, while PYGL knockdown has opposite effects. Mechanically, hypoxia induces PYGL expression in a hypoxia inducible factor 1α (HIF1α)-dependent manner and promotes glycogen accumulation. Elevated PYGL mobilizes accumulated glycogen to fuel glycolysis via its activity as a glycogen phosphorylase, thus inducing the EMT process, which could be suppressed by the glycolysis inhibitor 2-deoxy-D-glucose (2-DG). Clinically, PYGL expression is upregulated in PDAC and correlates with its malignant features and poor prognosis. Collectively, the data from our study reveal that the hypoxia/PYGL/glycolysis-induced EMT promotes PDAC metastasis, which establishes the rational for targeting hypoxia/PYGL/glycolysis/EMT signaling pathway against PDAC.

SUBMITTER: Ji Q

PROVIDER: S-EPMC10092766 | biostudies-literature | 2023

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

PYGL-mediated glucose metabolism reprogramming promotes EMT phenotype and metastasis of pancreatic cancer.

Ji Qian Q Li Hengchao H Cai Zhiwei Z Yuan Xiao X Pu Xi X Huang Yumeng Y Fu Shengqiao S Chu Liangmei L Jiang Chongyi C Xue Junli J Zhang Xiaoxin X Li Rongkun R

International journal of biological sciences 20230321 6

Epithelial-mesenchymal transition (EMT) is closely associated with tumor invasion and metastasis. However, key regulators of EMT in pancreatic ductal adenocarcinoma (PDAC) need to be further studied. Bioinformatics analyses of pancreatic cancer public datasets showed that glycogen phosphorylase L (PYGL) expression is elevated in quasimesenchymal PDAC (QM-PDAC) and positively associated with EMT. <i>In vitro</i> cellular experiments further confirm PYGL as a crucial EMT regulator in PDAC cells. F ...[more]

PMID: 37063425

Similar Datasets

Project description:Pancreatic ductal adenocarcinoma (PDAC) is characterized by its aggressive nature and dismal prognosis, largely attributed to its unique tumor microenvironment. However, the molecular mechanisms by which tumor-associated macrophages (TAMs) promote PDAC progression, particularly the role of β-catenin signaling in regulating TAM phenotype and function, remain incompletely understood. Initially, we performed comprehensive analyses of RNA-seq and single-cell RNA-seq (scRNA-seq) datasets to investigate OSM and LOXL2 expression patterns in PDAC. Subsequently, the regulatory relationship between β-catenin and OSM in TAMs was examined using THP-1-derived macrophages. Furthermore, the functional impact of TAM-derived OSM on PDAC progression was evaluated through in vitro co-culture systems and an in vivo Panc02 lung metastasis model. Additionally, mechanistic studies employed pharmacological inhibitors and genetic approaches targeting β-catenin, OSM, and STAT3 signaling. Notably, elevated expression of OSM and LOXL2 in PDAC specimens significantly correlated with poor patient survival. Intriguingly, scRNA-seq analysis revealed that β-catenin signaling was uniquely activated in TAMs among immune cells, which consequently regulated both TAM polarization and OSM expression. These OSM-expressing TAMs exhibited a distinct hybrid M1/M2 phenotype. Besides, our transcriptional profiling of TAMs revealed concurrent activation of both pro- and anti-inflammatory programs, with enrichment in Wnt signaling pathways. RNA-seq analysis of PDAC cells exposed to TAM-derived factors demonstrated enhanced mesenchymal transition and stemness properties, with direct enrichment of OSM signaling and extracellular matrix remodeling pathways. Mechanistically, β-catenin activation directly regulated both TAM phenotype and OSM expression, while TAM-conditioned medium enhanced PDAC cell migration, invasion, and lung metastasis. Importantly, inhibition of β-catenin signaling simultaneously altered TAM polarization and reduced OSM expression, which substantially attenuated epithelial-mesenchymal transition (EMT) in co-cultured PDAC cells. Moreover, STAT3 inhibition abolished OSM-induced LOXL2 expression and subsequent EMT programming. Collectively, we identified a novel β-catenin/OSM-STAT3/LOXL2 signaling axis mediating TAM-induced PDAC progression. This pathway not only elucidates a previously unrecognized mechanism of β-catenin-mediated regulation of TAM function and phenotype but also presents potential therapeutic targets for intervention.

Dataset Information

PYGL-mediated glucose metabolism reprogramming promotes EMT phenotype and metastasis of pancreatic cancer.

Publications

PYGL-mediated glucose metabolism reprogramming promotes EMT phenotype and metastasis of pancreatic cancer.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets