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Transcriptional profile of tumor associated macrophages in Ptenpc-/- and Ptenpc-/; Smad4pc-/- tumors

ABSTRACT: Tumor associated macrophages (TAMs) are correlated with the progression of prostatic adenocarcinoma (PCa) but are still poorly described in this context. Here we applied high dimensional single-cell RNA-seq to profile the transcriptional landscape of TAMs in PCa. We identified a subset of tumor infiltrating macrophages that shows a dysregulation in transcriptional pathways associated with lipid metabolism. In human and mouse models of PCa this subset of macrophages expresses the scavenger receptor MARCO and is characterized by accumulation of lipid droplets. We identified a gene signature derived from MARCO-expressing TAMs that correlates with PCa progression and is associated with shorter disease-free survival. Mechanistically, we observed that lipid accumulation in TAMs is promoted by the secretome of cancer cells. Lipid-loading confers on tumor-conditioned macrophages the capability to promote cancer cell migration mediated by CCL6. Importantly, administration of high fat diet to tumor-bearing mice raises lipid accumulation in TAMs and affects their transcriptional profile. Finally, we demonstrate that the accumulation of lipids in macrophages is dependent on MARCO expression and we show that MARCO blockade hinders tumor growth and invasiveness in models of advanced PCa. Our findings provide evidence that lipid-loaded TAMs represent a new therapeutic target in PCa.

ORGANISM(S): Mus musculus

PROVIDER: GSE153975 | GEO | 2022/02/16

REPOSITORIES: GEO

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Project description:Progression and relapse-free survival of ovarian carcinoma are associated with the abundance of immunosuppressed CD163highCD206high tumor-associated macrophages (TAMs) and high levels of polyunsaturated fatty acids (PUFAs), in particular arachidonic acid (AA), in the tumor microenvironment. In the present study, we have investigated whether both associations are functionally linked. Methods: The effect of PUFAs on cytokine-mediated pro-inflammatory signal transduction was studied in primary monocyte-derived macrophages (MDMs) by transcriptomics, bioinformatics, phosphoprotein analysis of signal transduction proteins and MS-based proteomics of lipid rafts. Results: Pathway analysis of transcriptional profiles revealed that high CD163 and CD206/MRC1 expression in TAMs is strongly associated with an inhibition of cytokine-triggered signal transduction. This is mirrored by an impairment of the transcriptional response to interferon-beta (IFNbeta), IFNgamma and IL-6 in monocyte-derived macrophages (MDMs) by AA. This AA-mediated inhibition of pro-inflammatory signaling is caused by dysfunctions of the cognate receptors, as indicated by the inhibition by PUFAs of JAK1, JAK2, STAT1 and STAT3 phosphorylation, with the strongest inhibitory effects exerted by AA and its non-metabolizable analog ETYA. AA/ETYA treatment of MDMs results in altered composition of lipid rafts, including reduced amounts of the interferon receptor IFNAR1, STAT1 and other immune-regulatory proteins. The AA-mediated inhibition of IFN-triggered STAT1 phosphorylation was reversed by water-soluble cholesterol, known to prevent the perturbation of lipid raft structure by PUFAs. Conclusion: Our data suggest that AA, and to a lesser degree other PUFAs, impair pro-inflammatory signaling in macrophages, at least in part by altering the structure of lipid rafts, and thereby contribute to the reeducation of tumor-associated macrophages. Our findings also suggest that the pharmacologic restoration of lipid raft functions in TAM may be a promising strategy for the development of new therapeutic approaches.

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Transcriptional profile of tumor associated macrophages in Ptenpc-/- and Ptenpc-/; Smad4pc-/- tumors

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