Proteomics

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Multi-omic Characterization of Pancreatic Cancer-Associated Macrophage Polarization Reveals Deregulated Metabolic Programs Driven by the GMCSF-PI3K Pathway


ABSTRACT: The pancreatic ductal adenocarcinoma (PDA) microenvironment is composed of a variety of cell types and marked by extensive fibrosis and inflammation. Tumor-associated macrophages (TAM) are abundant, and they are important mediators of disease progression and invasion. TAMs are polarized in situ to a tumor promoting and immunosuppressive phenotype via cytokine signaling and metabolic crosstalk from malignant epithelial cells and other components of the tumor microenvironment (TME). However, the specific distinguishing features and functions of TAMs remain poorly defined. Here, we generated tumor-educated macrophages (TEM) in vitro and performed detailed, multi-omic characterization (i.e. transcriptomics, proteomics, metabolomics). Our results reveal unique genetic and metabolic signatures of TEMs, the veracity of which were queried against our in-house single cell RNA sequencing (scRNA-seq) dataset of human pancreatic tumors. This analysis identified expression of novel, metabolic TEM markers in human pancreatic TAMs, including ARG1, ACLY, and TXNIP. We then utilized our TEM model system to study the role of mutant Kras signaling in cancer cells on TEM polarization. This revealed an important role for GM-CSF and lactate on TEM polarization, molecules released from cancer cells in a mutant Kras-dependent manner. Lastly, we demonstrate that GM-CSF dysregulates TEM gene expression and metabolism through PI3K-AKT pathway signaling. Collectively, our results define new markers and programs to classify pancreatic TAMs, how these are engaged by cancer cells, and the precise signaling pathways mediating polarization.

INSTRUMENT(S): Orbitrap Fusion

ORGANISM(S): Mus Musculus (mouse)

TISSUE(S): Macrophage

SUBMITTER: Ho-Joon Lee  

LAB HEAD: Costas A. Lyssiotis

PROVIDER: PXD028632 | Pride | 2022-02-16

REPOSITORIES: Pride

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UM_F_50cm_2018_0220.raw Raw
UM_F_50cm_2018_0220_0231.msf Msf
UM_F_50cm_2018_0221.raw Raw
UM_F_50cm_2018_0222.raw Raw
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Publications

Multiomic characterization of pancreatic cancer-associated macrophage polarization reveals deregulated metabolic programs driven by the GM-CSF-PI3K pathway.

Boyer Seth S   Lee Ho-Joon HJ   Steele Nina N   Zhang Li L   Sajjakulnukit Peter P   Andren Anthony A   Ward Matthew H MH   Singh Rima R   Basrur Venkatesha V   Zhang Yaqing Y   Nesvizhskii Alexey I AI   Pasca di Magliano Marina M   Halbrook Christopher J CJ   Lyssiotis Costas A CA  

eLife 20220214


The pancreatic ductal adenocarcinoma microenvironment is composed of a variety of cell types and marked by extensive fibrosis and inflammation. Tumor-associated macrophages (TAMs) are abundant, and they are important mediators of disease progression and invasion. TAMs are polarized in situ to a tumor promoting and immunosuppressive phenotype via cytokine signaling and metabolic crosstalk from malignant epithelial cells and other components of the tumor microenvironment. However, the specific dis  ...[more]

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