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Functionally and Metabolically Divergent Melanoma-Associated Macrophages Originate from Common Bone-Marrow Precursors

ABSTRACT: Melanomas display high numbers of tumor-associated macrophages (TAMs), which correlate with worse prognosis but also retain the potential to restore anti-tumor activity. Harnessing macrophages for therapeutic purposes has been particularly challenging due to their heterogeneity, based on their ontogeny and function and driven by the tissue-specific niche. In the present study, we used the YUMM1.7 murine melanoma model to better understand melanoma TAM origin and dynamics during tumor progression, with potential therapeutic implications. We identified distinct TAM subsets based on F4/80 expression, with the F4/80high fraction increasing over time and displaying tissue-resident-like phenotype. While skin-resident macrophages showed mixed ontogeny, F4/80+ TAM subsets in i.d. YUMM1.7 tumors originated almost exclusively from bone-marrow precursors. Multiparametric analysis of macrophage phenotype showed a temporal divergence of F4/80+ TAM subpopulations, which also differed from skin-resident subsets, and from their monocytic precursors. Overall, F4/80+ TAMs displayed co-expression of M1- and M2-like canonical markers, and RNA-seq and pathway analysis showed differential immunosuppressive and metabolic profiles. GSEA showed F4/80high TAMs to rely on oxidative phosphorylation, with increased proliferation and protein secretion while F4/80low cells had high pro-inflammatory and intracellular signaling pathways, with lipid and polyamine metabolism. Overall, the present in-depth characterization provides further evidence of the ontogeny of the evolving melanoma TAMs. Some of these gene profiles matched recently-identified TAM clusters in other tumor models and human cancers, which in turn can lead to more effective therapies targeting specific immunosuppressive cells in advanced tumor stages.

ORGANISM(S): Mus musculus

PROVIDER: GSE223545 | GEO | 2023/01/30

REPOSITORIES: GEO

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Project description:Tumor-associated macrophages (TAMs) are highly heterogeneous, derived from myeloid monocyte/macrophages or tissue-resident macrophages, and play vital role in tumor progression. Here we adopted a C57BL/6 mouse model imitating the late-stage colorectal liver metastasis (CRLM) by Mc38 colorectal cancer cell injection via the portal vein. We defined the critical period at 7 to 9 days post injection (dpi) for tumor neovascularization on serial sections of CRLM biopsies. The tumor neovascularization was initiated from one of the liver blood vessels via vessel cooption and extended by vascular mimicry and growth of CD34+cells. In samples with increasing sized liver metastases of CRLM, infiltrated Ly6C+ CD11b+ F4/80 monocytes steadily gained the expression of F4/80, a Kupffer cell marker, and then transformed into Ly6C CD11bint F4/80+ cells, which, the same phenotype was also adapted by Ly6C CD11b F4/80+ Kupffer cells. F4/80+ TAMs showed proximity to neovascularization and tumor vessels. Depletion of macrophages or disturbance on macrophage polarization during the crucial period of neovascularization impeded tumor growth and vascularization and resulted in greatly reduced F4/80+ TAMs, yet increased CD11b+ cells due to inhibition of TAM differentiation. In summary, we showed dynamic F4/80+ TAM differentiation within the tumor microenvironment and strengthened its role as perivascular TAMs in CRLM. A set of aliquot samples (about 0.25 cm3) from for flow cytometry preparations (the above method and Fig. 4A) were used for bulk RNA-Sequencing, among these samples, Ht1 and Ht3 were identical samples; F4/80+cells and CD11b+ cells were selected from medium-sized CRLM (Mt2) with microbeads and MS column;A total of 20 samples were sent for analysis. These collected tissues were flash-frozen in liquid nitrogen, stored at - 80°C and shipped on dry ice to the sequencing provider (Novogene, www.novogene.com), who then extracted RNA from these samples and confirmed that all sample RNA were in good quality and adequate concentrations. The resulted RNA-Sequencing data were verified as the clean reads > 95%, Q30 > 90%, and error rate < 0.05%; Square of Pearson Correlation Coefficient (R2) between the biological replicates was > 0.89; R2 of the identical samples (Ht-1 and Ht-3) was > 0.98.

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Functionally and Metabolically Divergent Melanoma-Associated Macrophages Originate from Common Bone-Marrow Precursors

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