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

BioRxiv : the Preprint Server for Biology
S. M. BoyerCostas A Lyssiotis

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 p...Continue Reading

Methods Mentioned

BETA
RNA-Seq
scRNA-seq
metabolomics profiling
histone acetylation
ELISA
PCA

Software Mentioned

MetaboAnalyst
TopHat
HTSeq
RNA
MSFragger
Integrator
Morpheus
Seq
Agilent MassHunter Workstation Quantitative Analysis
Bowtie2

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