Dataset Information

Pancreatic cancer-intrinsic HuR regulates the pro-tumorigenic properties of extracellular vesicles

ABSTRACT: Pancreatic ductal adenocarcinoma (PDAC) tumors contain chaotic vasculature that limits immune surveillance and promotes early events in the metastatic cascade. However, current antiangiogenic therapies have failed in PDAC, and it remains important to uncover mechanisms by which cancer cells signal to endothelial cells to increase angiogenesis. The tumor-intrinsic RNA-binding protein HuR (ELAVL1) plays an important role re-shaping the tumor microenvironment (TME) by regulating the stability and translation of cytokine encoding transcripts. PDAC-intrinsic HuR influenced endothelial cell function in the TME via extracellular vesicle (EV) signaling, an underexplored signaling axis in tumor progression. HuR knockout (KO) tumors had impaired growth in an immunocompetent mouse model, and that administering purified wildtype (WT) EVs increased tumor growth. Further, isobaric-labeling quantitative proteomics showed that PDAC EVs contained HuR-dependent cargos relating to endothelial cell function and angiogenesis. Treatment of endothelial cells with HuR WT EVs strongly increased the expression of genes involved in barrier function, endothelial cell development, and directly increased their migratory and tube forming functions. In an immunocompetent orthotopic mouse model of PDAC, HuR increased endothelial cell presence and sprouting, while decreasing ICAM-1 expression. When utilizing the PalmGRET genetic EV reporter, decreased ICAM-1 within WT tumors occurred in endothelial cells that had imported PDAC EVs, suggesting signaling that directly modulates endothelial cell behavior in vivo. Collectively, our data reveal a new role of HuR in EV signaling to endothelial cells, promoting angiogenesis while restricting endothelial cell leukocyte trafficking behavior.

INSTRUMENT(S):

ORGANISM(S): Homo Sapiens (human)

DISEASE(S): Pancreatic Ductal Adenocarcinoma

SUBMITTER: Phillip Wilmarth

LAB HEAD: Jonathan R. Brody

PROVIDER: PXD059674 | Pride | 2025-08-09

REPOSITORIES: Pride

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Dataset's files

Source:

			Action	DRS
	2024.04_UP000005640_9606_Homo_sapiens_canonical_both.fasta	Fasta
	BROD-1355_QC_checks.html	Other
	BROD-1355_analysis.pptx	Other
	BROD-1355_edgeR-exact.html	Other
	BROD-1355_grouped_proteins_TMT.xlsx	Xlsx

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Publications

Post-transcriptional regulator HuR promotes immune evasion in pancreatic ductal adenocarcinoma.

Guo Yifei Y Finan Jennifer M JM Bartlett Alexandra Q AQ Sivagnanam Shamilene S Blise Katie E KE Kirchberger Nell N Betre Konjit K McCarthy Grace A GA Hawthorne Kevin K Chen Canping C Grossberg Aaron A Xia Zheng Z Coussens Lisa M LM Sears Rosalie C RC Brody Jonathan R JR Eil Robert R

bioRxiv : the preprint server for biology 20250413

The tumor microenvironment (TME) of pancreatic ductal adenocarcinoma (PDAC) is characterized by a limited infiltration of tumor-specific T cells and anti-tumor T cell activity. Extracellular factors in the PDAC TME have been widely reported to mediate immune suppression, but the contribution from tumor-intrinsic factors is not well understood. The RNA-binding protein, HuR (ELAVL1), is enriched in PDAC and negatively correlates with T cell infiltration. In an immunocompetent Kras-p53-Cre (KPC) or ...[more]

PMID: 40291674

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Project description:Background: Carotid atherosclerosis is a multifaceted disease orchestrated by a myriad of cell-cell communication that drives progression along a clinical continuum (asymptomatic to symptomatic). Extracellular vesicles (EVs) are lipid bilayer membrane-enclosed cell-derived nanoparticles that represent a new paradigm in cellular communication. Little is known about their biological cargo, cellular origin/destination, and functional roles in human atherosclerotic plaque. Methods: EVs were enriched via size exclusion chromatography from human carotid endarterectomy samples dissected into plaque and marginal zones (n= 29 patients, paired plaque and marginal zone; symptomatic n=16, asymptomatic n=13), with further density gradient ultracentrifugation for proteomic analysis. EV cargoes were assessed via whole transcriptome miRNA sequencing and mass spectrometry-based proteomics. EV multi-omics were integrated with publicly available bulk and single cell RNA-sequencing (scRNA-seq) datasets to predict EV cellular origin and ligand-receptor interactions and multi-modal biological network integration of EV-cargo was completed. EV functional impact was assessed with endothelial angiogenesis assays. Results: Human carotid plaques contained greater quantities of EVs than adjacent marginal zones. EV-miRNA and protein content was different in diseased plaque versus adjacent marginal zones, with differential functions in key atherogenic pathways. EV cellular origin analysis suggested that tissue EV signatures originated from endothelial cells (EC), smooth muscle cells (SMC), and immune cells. Furthermore, EV signatures from SMCs and immune cells were most enriched in the marginal and plaque zones, respectively. Integrated tissue vesiculomics and scRNA-seq indicated complex EV-vascular cell communication strategies that changed with disease progression and plaque vulnerability (symptomatic disease). Plaques from symptomatic patients, but not asymptomatic patients, were characterized by increased involvement of endothelial pathways and more complex ligand-receptor interactions, relative to their marginal zones. Plaque-EVs were predicted to mediate communication with ECs and together with pathway enrichment analysis delineated a strong endothelial signature with potential roles in angiogenesis and neovascularization – well-known indices of plaque instability. This was corroborated functionally, wherein human carotid symptomatic plaque EVs induced sprouting angiogenesis (number and length of sprouts) in comparison to their matched marginal zones. Conclusion: Our findings indicate that EVs may drive dynamic changes in plaques through EV-vascular cell communication and effector functions that typify vulnerability to rupture, precipitating symptomatic disease. The discovery of endothelial-directed processes mediated by EVs creates new avenues for novel therapeutics in atherosclerosis.