Dataset Information

Eicosanoids in the pancreatic tumor microenvironment - a multicellular, multifaceted progression.

ABSTRACT:

Background and aims

Eicosanoids, oxidized fatty acids that serve as cell-signaling molecules, have been broadly implicated in tumorigenesis. Here, we aimed to identify eicosanoids associated with pancreatic tumorigenesis and the cell types responsible for their synthesis.

Methods

We profiled normal pancreas and pancreatic ductal adenocarcinoma (PDAC) in mouse models and patient samples using mass spectrometry. We interrogated RNA sequencing datasets for eicosanoid synthase or receptor expression. Findings were confirmed by immunostaining.

Results

In murine models, we identified elevated levels of PGD₂, prostacyclin, and thromboxanes in neoplasia while PGE₂, 12-HHTre, HETEs, and HDoHEs are elevated specifically in tumors. Analysis of scRNA-seq datasets suggests that PGE₂ and prostacyclins are derived from fibroblasts, PGD₂ and thromboxanes from myeloid cells, and PGD₂ and 5-HETE from tuft cells. In patient samples, we identified a transition from PGD₂ to PGE₂-producing enzymes in the epithelium during the transition to PDAC, fibroblast/tumor expression of PTGIS, and myeloid/tumor cell expression of TBXAS1.

Conclusions

Our analyses identify key changes in eicosanoid species during pancreatic tumorigenesis and the cell types that contribute to their synthesis. Thromboxane and prostacyclin expression is conserved between animal models and human disease and may represent new druggable targets.

SUBMITTER: Gubbala VB

PROVIDER: S-EPMC9583893 | biostudies-literature | 2022

REPOSITORIES: biostudies-literature

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Publications

Eicosanoids in the pancreatic tumor microenvironment - a multicellular, multifaceted progression.

Gubbala Vikas B VB Jytosana Nidhi N Trinh Vincent Q VQ Maurer H Carlo HC Naeem Razia F RF Lytle Nikki K NK Ma Zhibo Z Zhao Steven S Lin Wei W Han Haiyong H Shi Yu Y Hunter Tony T Singh Pankaj K PK Olive Kenneth P KP Tan Marcus C B MCB Kaech Susan M SM Wahl Geoffrey M GM DelGiorno Kathleen E KE

Gastro hep advances 20220611 4

<h4>Background and aims</h4>Eicosanoids, oxidized fatty acids that serve as cell-signaling molecules, have been broadly implicated in tumorigenesis. Here, we aimed to identify eicosanoids associated with pancreatic tumorigenesis and the cell types responsible for their synthesis.<h4>Methods</h4>We profiled normal pancreas and pancreatic ductal adenocarcinoma (PDAC) in mouse models and patient samples using mass spectrometry. We interrogated RNA sequencing datasets for eicosanoid synthase or rece ...[more]

PMID: 36277993

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Project description:BackgroundTo date, a growing body of evidence suggests that unfolded protein response (UPR) sensors play a vital role in carcinogenesis. However, it remains unclear whether they are involved in pancreatic ductal adenocarcinoma (PDAC) and how they relate to clinical outcomes. This study aims to investigate the biological function and mechanism of how a novel UPR sensor, CREB3L1 works in PDAC and further evaluate its clinical application prospect.MethodsWe tested UPR signaling including CREB3L1 in Thapsigargin-treated PDAC cells. Subsequently, we defined CREB3L1 expression and further analyzed its expression with clinical characteristics in PDAC. Then, we established gene-modified cells to determine whether CREB3L1 functions in cell proliferation and migration capacity. Besides, we constructed subcutaneously and orthotopically transplanted mice models to verify their progrowing function and pulmonary metastasis models to prove their proinvasion role. What's more, RNAseq, qPCR, Western blotting, immunohistochemistry and multicolor flow cytometry experiments were used to explore the mechanism of how CREB3L1 worked in PDAC. Lastly, CREB3L1 expression correlation with PDAC immunotherapy outcome and immune cell signatures were explored in the patients with advanced PDAC who received PD-1 antibody therapy.ResultsWe first confirmed CREB3L1 could be induced by endoplasmic reticulum stressor and found its aberrant activation was associated with poorer overall survival in PDAC patients indicating the protumor function of the new UPR sensor. Functionally, we confirmed CREB3L1 contributing to PDAC malignant progression including growth and metastasis by multiple in in vitro and in vivo models. Mechanistically, CREB3L1 upregulated COL3A1 and promoted dense stroma formation for facilitating PDAC and knocking down COL3A1 disrupted CREB3L1 protumor function. Furthermore, CREB3L1-induced TAM polarization toward an M2 phenotype and reduced the infiltration of CD8+ T cells. Clinically, CREB3L1 correlated with immune cell signatures as well as immune checkpoint blockade (ICB) treatment response and outcome that CREB3L1aberrant activation indicated poorer efficacy and worse prognosis than the low in PDAC which might empower clinical decision.ConclusionsCollectively, this study revealed CREB3L1 facilitated PDAC progression, shaped an immune exclude tumor microenvironment and distinguished therapy response and outcome of ICB therapy indicating CREB3L1 could be a promising novel molecular target and biomarker for PDAC treatment.

Dataset Information

Eicosanoids in the pancreatic tumor microenvironment - a multicellular, multifaceted progression.

Background and aims

Methods

Results

Conclusions

Publications

Eicosanoids in the pancreatic tumor microenvironment - a multicellular, multifaceted progression.

Similar Datasets

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