PXD021038-2

PXD021038 is an original dataset announced via ProteomeXchange.

Title	Phosphoproteomics identify arachidonic-acid-regulated signal transduction pathways modulating macrophage functions in ovarian cancer
Description	Arachidonic acid (AA) is a polyunsaturated fatty acid present at high concentrations in the ovarian cancer (OC) microenvironment and is associated with poor clinical outcome. In the present study, we elucidate a potential link between AA and pro-tumorigenic macrophage polarization. Methods: AA-triggered signal transduction was studied in primary monocyte-derived macrophages (MDMs) by phosphoproteomics, transcriptional profiling, measurement of intracellular Ca2+ accumulation and reactive oxygen species production in conjunction with bioinformatic analyses. Functional effects were investigated by actin filament staining, quantification of macropinocytosis and analysis of extracellular vesicle release. Results: We identified the ASK1 - p38 (MAPK13/14) axis as a central constituent of signal transduction pathways triggered by non-metabolized AA. This pathway was induced by the Ca2+-triggered activation of calmodulin kinase II, and to a minor extent by ROS generation in a subset of donors. Activated p38 in turn was linked to a transcriptional stress response associated with a poor relapse-free survival. Consistent with the phosphorylation of the p38 substrate HSP27 and the (de)phosphorylation of multiple regulators of Rho family GTPases, AA impaired actin filament organization and inhibited actin-driven macropinocytosis. AA also affected the phosphorylation of proteins regulating vesicle biogenesis, and consistently, AA enhanced the release of tetraspanin-containing exosomes. Finally, we identified phospholipase A2 Group 2A (PLA2G2A) as the clinically most relevant enzyme producing extracellular AA, providing further potentially theranostic options. Conclusion: Our results suggest that AA contributes to an unfavorable clinical outcome of OC by promoting the pro-tumorigenic phenotype of tumor-associated macrophages. Besides critical AA-regulated signal transduction proteins identified in the present study, PLA2G2A might represent a potential prognostic tool and therapeutic target to interfere with OC progression.
HostingRepository	PRIDE
AnnounceDate	2020-10-05
AnnouncementXML	Submission_2021-10-26_22:50:25.616.xml
DigitalObjectIdentifier
ReviewLevel	Peer-reviewed dataset
DatasetOrigin	Original dataset
RepositorySupport	Unsupported dataset by repository
PrimarySubmitter	Johannes Graumann
SpeciesList	scientific name: Homo sapiens (Human); NCBI TaxID: 9606;
ModificationList	TMT6plex-126 reporter+balance reagent acylated residue; phosphorylated residue; acetylated residue; monohydroxylated residue; iodoacetamide derivatized residue
Instrument	Q Exactive

Revision	Datetime	Status	ChangeLog Entry
0	2020-08-20 23:14:34	ID requested
1	2020-10-05 00:36:28	announced
⏵ 2	2021-10-26 22:50:26	announced	2021-10-27: Updated publication reference for PubMed record(s): 33391540.
3	2021-10-29 04:24:51	announced	2021-10-29: Updated project metadata.

Dietze R, Hammoud MK, G, ó, mez-Serrano M, Unger A, Bieringer T, Finkernagel F, Sokol AM, Nist A, Stiewe T, Reinartz S, Ponath V, Preu, ß, er C, von Strandmann EP, M, ü, ller-Br, ü, sselbach S, Graumann J, M, ü, ller R, Phosphoproteomics identify arachidonic-acid-regulated signal transduction pathways modulating macrophage functions with implications for ovarian cancer. Theranostics, 11(3):1377-1395(2021) [pubmed]

submitter keyword: ovarian cancer

arachidonic acid

macrophages

Rolf Müller
contact affiliation	Tranlational Oncology Group, Center for Tumor Biology and Immunology, Philipps University, Marburg, Germany
contact email	rolf.mueller@uni-marburg.de
lab head
Johannes Graumann
contact affiliation	Max Planck Institute for Heart and Lung Research
contact email	johannes.graumann@mpi-bn.mpg.de
dataset submitter

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PRIDE project URI

• PRIDE
  1. PXD021038
     1. Label: PRIDE project
     2. Name: Phosphoproteomics identify arachidonic-acid-regulated signal transduction pathways modulating macrophage functions in ovarian cancer