Tissue-resident macrophages in omentum promote metastatic spread of ovarian cancer

doi:10.1084/jem.20191869

. 2020 Apr 6;217(4):e20191869.

doi: 10.1084/jem.20191869.

Tissue-resident macrophages in omentum promote metastatic spread of ovarian cancer

Anders Etzerodt^{1

2}, Morgane Moulin^{1

3}, Thomas Koed Doktor⁴, Marcello Delfini¹, Noushine Mossadegh-Keller¹, Marc Bajenoff¹, Michael H Sieweke^{1

5}, Søren Kragh Moestrup^{2

6}, Nathalie Auphan-Anezin¹, Toby Lawrence^{1

3

7}

Affiliations

¹ Aix Marseille Univ, CNRS, INSERM, CIML, Marseille, France.
² Department of Biomedicine, University of Aarhus, Aarhus, Denmark.
³ Centre for Inflammation Biology and Cancer Immunology, School of Immunology & Microbial Sciences, King's College London, London, UK.
⁴ Department of Biochemistry and Molecular Biology, University of Southern Denmark, Odense, Denmark.
⁵ Centre for Regenerative Therapies, TU Dresden, Dresden, Germany.
⁶ Institute of Molecular Medicine, University of Southern Denmark, Odense, Denmark.
⁷ Henan Key Laboratory of Immunology and Targeted Therapy, School of Laboratory Medicine, Xinxiang Medical University, Xinxiang, China.

PMID: 31951251
PMCID: PMC7144521
DOI: 10.1084/jem.20191869

Tissue-resident macrophages in omentum promote metastatic spread of ovarian cancer

Anders Etzerodt et al. J Exp Med. 2020.

. 2020 Apr 6;217(4):e20191869.

doi: 10.1084/jem.20191869.

Authors

Affiliations

¹ Aix Marseille Univ, CNRS, INSERM, CIML, Marseille, France.
² Department of Biomedicine, University of Aarhus, Aarhus, Denmark.
³ Centre for Inflammation Biology and Cancer Immunology, School of Immunology & Microbial Sciences, King's College London, London, UK.
⁴ Department of Biochemistry and Molecular Biology, University of Southern Denmark, Odense, Denmark.
⁵ Centre for Regenerative Therapies, TU Dresden, Dresden, Germany.
⁶ Institute of Molecular Medicine, University of Southern Denmark, Odense, Denmark.
⁷ Henan Key Laboratory of Immunology and Targeted Therapy, School of Laboratory Medicine, Xinxiang Medical University, Xinxiang, China.

PMID: 31951251
PMCID: PMC7144521
DOI: 10.1084/jem.20191869

Abstract

Experimental and clinical evidence suggests that tumor-associated macrophages (TAMs) play important roles in cancer progression. Here, we have characterized the ontogeny and function of TAM subsets in a mouse model of metastatic ovarian cancer that is representative for visceral peritoneal metastasis. We show that the omentum is a critical premetastatic niche for development of invasive disease in this model and define a unique subset of CD163+ Tim4+ resident omental macrophages responsible for metastatic spread of ovarian cancer cells. Transcriptomic analysis showed that resident CD163+ Tim4+ omental macrophages were phenotypically distinct and maintained their resident identity during tumor growth. Selective depletion of CD163+ Tim4+ macrophages in omentum using genetic and pharmacological tools prevented tumor progression and metastatic spread of disease. These studies describe a specific role for tissue-resident macrophages in the invasive progression of metastatic ovarian cancer. The molecular pathways of cross-talk between tissue-resident macrophages and disseminated cancer cells may represent new targets to prevent metastasis and disease recurrence.

PubMed Disclaimer

Conflict of interest statement

Disclosures: Dr. Etzerodt reported personal fees from Stipe Therapeutics outside the submitted work. No other disclosures were reported.

Figures

**Figure 1.**
**Omentum is a critical premetastatic niche for ovarian cancer cells.** **(A)** Location of the omentum in the abdominal cavity of mice. **(B)** In vivo bioluminescence imaging of mice at 1, 21, 35, and 63 d after i.p. injection of 10⁶ ID8-Luc cells; scale bar: 1 cm. **(C)** H&E stain of frozen omental sections from naive mice or 35 and 63 d after injection of ID8-Luc cells; scale bar: 100 µm. **(D)** Ex vivo luminescence analysis of omentum and ascites. RLU, relative luminescent unit. Data are represented as mean ± SEM of n = 5, and statistically significant difference was calculated using two-way ANOVA followed by Tukey post hoc test; ***, P < 0.001. **(E)** Tumor nodules on the diaphragm of mice 10 wk after injection of ID8-Luc cells. **(F)** In vivo bioluminescence analysis of omentectomized, sham-operated, or control (Ctrl) mice from 0–63 d after injection of ID8-Luc cells. cps, counts per second. Data are represented as mean ± SEM of n = 5, and statistically significant difference was calculated using two-way ANOVA followed by Tukey post hoc test; **, P < 0.01. **(G)** End-point analysis of malignant ascites in omentectomized or control mice 63 d after injection of ID8-Luc cells. Data are represented as mean ± SEM of n = 5, and statistically significant difference was calculated using Kruskal-Wallis one-way ANOVA followed by Dunn’s multiple comparisons test; *, P < 0.05. All data are representative of two independent experiments.

**Figure 2.**
**Single-cell transcriptional profiling of omental macrophages after tumor colonization.** **(A)** Whole-mount confocal imaging of omentum showing the location of FALCs by visualizing collagen IV (ColIV, green), adipocytes (LipidTox, red), and leukocyte clusters (CD45, white); scale bar: 0.5 mm. **(B)** Whole-mount imaging of ID8-Luc infiltration in the omentum 24 h after injection of ID8 cells. Pecam-1 staining for blood vessels (red), CD163 for macrophages (green), CD45 for FALCs (white), and Qdot⁷⁰⁵ for ID8 cells (magenta); scale bar: 100 µm and 50 µm in magnification. **(C)** Two-dimensional representation and clustering of single-cell TAM transcriptomes using UMAP (n = 16,514). **(D)** Heatmap showing the top 10 DEGs in each UMAP cluster. **(E)** Violin plots showing expression of commonly used macrophage markers.

**Figure 3.**
**Characterization of macrophage subsets in omentum by flow cytometry and confocal microscopy.** **(A)** Flow cytometry analysis of the myeloid cell compartment in omentum. Myeloid cells are gated as (i) Live, CD45.2⁺, singlets, Lin^neg (CD5, CD19, NK1.1, Ly6G, Siglec F), CD11b⁺, and subsequently macrophages were gated as F4/80⁺, CD64⁺. Monocytes were gated as (ii) F4/80⁻, CD64⁻, CCR2⁺. F4/80⁻, CD64⁻, and CCR2⁻ CD11b⁺ myeloid cells were designated as other. F4/80⁺ CD64⁺ macrophages were further gated based on (iii) CD169 and Lyve-1 expression, and finally CD169^hi Lyve-1⁺ cells were further divided into four subpopulations based on (iv) CD163 and Tim4 expression. SSC-A, side scatter area. **(B)** Whole-mount imaging of FALCs (CD45, white; CD169⁺, red; CD163⁺, green) in the omentum; scale bar: 100 µm. **(C)** Whole-mount imaging of FALCs (CD45, white; CD163⁺, green; Tim4⁺, red) in omentum; scale bar: 50 µm. **(D)** Flow cytometry analysis and relative distribution of CD11b⁺ myeloid cell populations shown in A, i–iii during tumor growth. **(E)** Flow cytometry analysis and relative distribution of CD169^hi Lyve-1⁺ macrophage subsets shown in A, iv during tumor growth. Whole-mount confocal imaging analysis is representative of n = 4 in two independent experiments. Flow cytometric data are represented as mean ± SEM of n = 4 and are representative of two independent experiments.

**Figure S1.**
**Gating strategy and expression of Tim4 and CD163 on omental macrophages**. (A) Gating strategy for the myeloid cell compartment excluding neutrophils. Myeloid cells were gated as Live (forward scatter area [FSC-A] versus Sytox Blue), CD45.2⁺ (CD45.2 versus SSC-A), CD5⁻, CD19⁻ (CD5 versus CD19), Lin^{neg(NK1.1, Ly6G)}, CD11b⁺ (CD11b versus Lineage), single cells (forward scatter height [FSC-H] versus forward scatter width [FSC-W]), and CD64⁺ and F4/80⁺ (F4/80 versus CD64). **(B)** Expression of CD163 and Tim4 among F4/80⁺ CD64⁺ macrophages that are CD169^negLyve-1^neg (green), CD169^int Lyve-1^neg (red), or CD169^hi Lyve-1^pos (blue). Data are representative of two independent experiments.

**Figure 4.**
**Embryonic origin of tissue-resident CD163⁺ Tim4⁺ macrophages in omentum.** **(A)** Analysis of macrophage ontogeny in ID8 tumor-bearing mice using shielded chimeras; host CD45.1 congenic mice were placed in a protective lead shield with only the hind legs exposed, before irradiation at 9 Gy. The following day, mice were reconstituted with donor bone marrow cells from CD45.1/.2 F1 mice. 5 wk after reconstitution, mice were injected with 10⁶ ID8-Luc cells i.p. At 8 wk after tumor injection, omentum was collected for analysis by flow cytometry. **(B)** Analysis of CD163 and Tim4 expression among CD169^hi Lyve-1⁺ macrophages in omentum from naive and tumor-bearing chimeric mice. **(C)** Chimerism was calculated as the proportion of CD45.1/.2⁺ CD169^hi Lyve-1⁺ macrophages relative to CD45.1/.2⁺ expression among Ly6C^hi blood monocytes. Data are represented as mean ± SEM of n = 5, and statistically significant difference was calculated using two-way ANOVA followed by Tukey post hoc test; ***, P < 0.001. **(D and E)** Flow cytometry analysis of Cx3Cr1-GFP expression in CD169^hi Lyve-1⁺ macrophages (P1–4; D) and CCR2⁺ monocytes (E). **(F)** Fate-mapping of Cx3Cr1-expressing monocytes in *Cx3cr1-R26^tdRFP* mice inoculated with ID8-Luc cells. Mice were injected with ID8-Luc i.p., and after 8 wk, 1 mg of tamoxifen was administered by oral gavage, and RFP expression was analyzed in CD169^hi Lyve-1⁺ macrophages 10 d later. Data are represented as mean ± SEM of n = 4. **(G)** Analysis of CD169^hi Lyve-1⁺ macrophage ontogeny by pulse-labeling of *Cx3Cr1⁻R26^YFP* embryos with tamoxifen at E16.5. **(H)** Omentum was harvested and analyzed by flow cytometry 8 wk after birth. **(I)** The percentage of YFP⁺ cells was calculated relative to YFP⁺ microglia. Data are represented as mean ± SEM of n = 6. All data are representative of two independent experiments.

**Figure S2.**
**Fate mapping of omental macrophages**. **(A and B)** Flow cytometric analysis of blood monocytes in mice 5 wk (A) or 13 wk (B) after adoptive transfer of CD45.1⁺/CD45.2⁺ donor bone marrow in irradiated CD45.1⁺ host mice that were protected by a lead shield. Monocytes were gated as Live (FSC-A versus Sytox Blue), CD5^neg, CD19^neg (CD5 versus CD19), NK1.1^neg, CD11b⁺ (CD11b versus NK1.1), and Ly6C⁺, Ly6G^neg (Ly6C versus Ly6G). Data are represented as mean ± SEM of n = 5. **(C)** Flow cytometric analysis of YFP⁺ microglia in Cx3Cr1CreER:R26-yfp mice pulse-labeled with tamoxifen at E16.5. Microglia were gated as Live (FSC-A versus Sytox Blue), Ly6C^neg, CD11c^neg (Ly6C versus CD11c), and CD45.2^dim, CD11b^hi (CD11b versus CD45.2). Data are represented as mean ± SEM of n = 6. All data are representative of two independent experiments.

**Figure 5.**
**CD163⁺ Tim4⁺ tissue-resident macrophages express a unique transcriptional profile.** **(A)** Gating strategy for cell sorting of P1, P2, and P3 populations of omental macrophages from naive (n = 2) and tumor-bearing mice at 5 and 10 wk after injection of ID8 cells (n = 4). 500 cells were sorted for each population and subjected to bulk RNAseq analysis. **(B)** PCA and network analysis of variable gene expression in P1, P2, and P3 macrophages. PCA analysis was performed on normalized data (mean = 0, and variance = 1), generating a correlation-based PCA plot. Network analysis connects k nearest neighbors (k = 3) based on similarity calculated by Pearson correlation. **(C)** Heatmap showing hierarchical clustering of the 5,000 most DEGs for each of the three populations at 10 wk of tumor growth. DEGs were identified by pairwise comparison with a cut-off of P_adjusted > 0.01. **(D)** SOMs of identified DEGs using the Kohonen package for R. The SOM analysis found 16 single SOMs that were subsequently grouped by hierarchical clustering to identify population-specific clusters (clusters 1–7). The magnitude of the pie slices indicates the relative proportions of genes enriched in P1 (green), P2 (brown), and P3 (blue) within the SOM. **(E)** ClusterProfiler enrichment analysis against the GO database on SOM clusters 1–7. Only clusters with significantly enriched pathways are visualized. Libraries were prepared from two independent experiments with n = 2 and sequenced on the same flow cell for a total of four biological replicates. ERAD, endoplasmic reticulum–associated protein degradation; pos, positive.

**Figure S3.**
**Hierarchical clustering analysis of omental macrophages**. **(A)** Heatmap showing hierarchical clustering analysis of the 5,000 most DEGs in P1 (green), P2 (red), and P3 (blue) CD169^hi Lyve-1^pos omental macrophages sorted at steady state (0 wk) or 5 wk and 10 wk after infiltration of ID8 ovarian cancer cells. **(B)** Heatmap showing expression of macrophage markers from transcriptomic analysis of P1 (green), P2 (red), and P3 (blue) CD169^hi Lyve-1^pos omental macrophages sorted 10 wk after ID8 injection (Fig. 2 E). Libraries were prepared from two independent experiments with n = 2 and sequenced on the same flow cell for a total of four biological replicates.

**Figure S4.**
**Depletion of monocyte-derived and tissue-resident omental macrophages**. **(A and B)** Flow cytometric analysis of CD169^hi Lyve-1^pos omental macrophages in *Ccr2*^−/− mice 10 wk after i.p. injection of 106 ID8 ovarian cancer cells. Data are represented as mean ± SEM of n = 5, and statistically significant difference was calculated using two-way ANOVA followed by Tukey post hoc test; *, P < 0.05; ****, P < 0.0001. **(C and D)** Omentum weight (C) and number of tumor cells in ascites (D) of WT and *Ccr2*^−/− mice 10 wk after injection of ID8 cells. Data are represented as mean ± SEM of n = 6, and statistically significant difference was calculated using Mann-Whitney U test; *, P < 0.05. **(E–G)** Flow cytometric analysis of CD169^hi Lyve-1^pos omental macrophages in *Cd163-Csf1r*^DTR mice 1 d (E) or 6 d (F and G) after i.p. injection of 4 ng/kg DT. CD169^hi Lyve-1^pos omental macrophages were gated as described in Fig. S1 A. **(H)** Flow cytometric analysis of peritoneal macrophages in *Cd163-Csf1r*^DTR and control mice 6 d after i.p. injection of 4 ng/kg DT. Peritoneal macrophages were gated as Live, CD45.2^pos, Lin^{neg(CD5,CD19, Ly6G, NK1.1)} CD11b⁺, F4/80⁺, and MHCII^neg. Data are represented as mean ± SEM of n = 7, and statistically significant difference was calculated using Mann-Whitney U test; *, P < 0.05. All data are representative of two independent experiments.

**Figure 6.**
**Specific depletion of CD163⁺ Tim4⁺ tissue-resident macrophages prevents metastatic spread of ovarian cancer.** **(A)** Cohorts of *Cd163-Csf1r^DTR* or control mice (*Csf1r^LSL-DTR*) were injected with 4 ng/kg DT 6 d before transplantation with ID8 cells. Mice were analyzed for depletion of macrophages and effects on tumor growth at 10 wk. **(B and C)** Flow cytometry analysis of CD163^hi Lyve-1⁺ macrophages in omentum of *Cd163-Csf1r^DTR* and *Csf1r^LSL-DTR* mice 10 wk after injection of ID8 cells. **(D–F)** Omentum weight (D), total tumor cells in ascites (E), and ascites volume (F) in *Cd163-Csf1r^DTR* and *Csf1r^LSL-DTR* mice treated with DT. **(G and H)** Ex vivo bioluminescence analysis of metastases on the diaphragm of *Cd163-Csf1r^DTR* and *Csf1r^LSL-DTR*; scale bar: 0.5 cm. Data are represented as mean ± SEM of n = 7, and statistically significant difference was calculated using Mann-Whitney U test; *, P < 0.05; **, P < 0.01; ***, P < 0.001. **(I)** Therapeutic depletion of CD163⁺ macrophages; mice were injected with ID8 cells and after 5 wk randomized into groups and treated with dxr-loaded αCD163-LNPs (αCD163-dxr), empty αCD163-LNPs (αCD163-ctrl), or PBS alone twice a week for 5 wk. **(J)** Tumor burden monitored by in vivo bioluminescent imaging. Data are represented as mean ± SEM of n = 6, and statistically significant difference was calculated using two-way ANOVA followed by Tukey post hoc test; *, P < 0.05; ***, P < 0.001. **(K)** Flow cytometry analysis of P1–P4 macrophages in omentum after therapeutic depletion of CD163⁺ cells. **(L–N)** Omentum weight (L), total tumor cells in ascites (M), and ascites volume (N). Data are represented as mean ± SEM of n = 6, and statistically significant difference was calculated using Kruskal-Wallis one-way ANOVA followed by Dunn’s multiple comparisons test; *, P < 0.05; **, P < 0.01; ***, P < 0.001. All data are representative of three independent experiments.

**Figure S5.**
**Transcriptomic analysis of ID8 ovarian cancer cells and TAMs from omentum**. (A–D) Heatmaps showing expression of genes associated with the enriched pathways in Fig. 5 E: Positive regulation of JAK-STAT (A), angiogenesis (B), regulation of tissue remodeling (C), and T cell differentiation (D). **(E)** GO term enrichment analysis of RNAseq data comparing cultured ID8 cells (n = 4) and ID8 cells harvested from ascites 11 wk after transplantation in vivo (ID8-A11, n = 4). Identified GO terms are represented by nodes with a size according to the number of enriched genes. Nodes are colored according to the normalized enrichment score (NES). **(F)** GSEA comparing ID8 and ID8-A11 against the hallmark gene sets in MSigDB. **(G)** Flow cytometric analysis of CSC markers CD54, CD55, CD106, and CD117 on tumor cells from ascites of mice specifically depleted of Tim4⁺ CD163⁺ resident TAM (αCD163-dxr). Mice were injected i.p. with 1 mg/kg αCD163-dxr or controls (empty αCD163-LNP or PBS) on days 1, 3, and 5, before injection of ID8-Luc cells i.p. on day 8. 10 wk after ID8, tumor cells in ascites were harvested and analyzed for CSC marker expression by flow cytometry by gating on Live, CD45.2^neg, and Lin^{neg(CD11b, F4/80, CD5,CD19, Ly6G, NK1.1)} cells. **(H)** Heatmap showing expression levels of TFs involved in EMT and MET in ID8 and ID8-A11 cells. All data are representative of three independent experiments.

**Figure 7.**
**Ovarian cancer cells in ascites acquire CSC characteristics.** **(A)** Heatmap showing expression of CSC markers in omental ID8 cells (ID8-OM) and ID8 cells from ascites (ID8-A11); see Table S1 for details. **(B)** Flow cytometry analysis of CSC surface markers on ascitic ID8-A11 cells compared with ID8 cells in omentum (ID8-OM). **(C and D)** Spheroid formation assay comparing cultured ID8 and ID8-A11 cells; 4 × 10⁴ cells were seeded in ultra-low-adherence 96-well plates, and formation of spheroids was assessed with a wide-field microscope. **(E)** Analysis of ALDH activity in ID8 and ID8-A11 cells by flow cytometry using the Aldefluor assay. ALDH⁺ cells were gated using DEAB-treated cells as negative control (left), and relative ALDH activity was calculated by measuring the median fluorescence intensity of Aldefluor. Data are represented as mean ± SEM of n = 5 (ID8) or n = 8 (ID8-A11), and statistically significant difference was calculated using Mann-Whitney U test; *, P < 0.05; **, P < 0.01. **(F)** Analysis of tumorigenic potential of ID8 and ID8-A11 cells in vivo; total tumor burden was monitored by in vivo bioluminescence imaging. Data are represented as mean ± SEM of n = 6, and statistically significant difference was calculated using two-way ANOVA followed by Tukey post hoc test; **, P < 0.01; ****, P < 0.0001. **(G)** Representative images of tumor localization at 30 d after injection of parental ID8-Luc and ID8-A11 cells; scale bar: 1 cm. **(H and I)** Ex vivo analysis of tumor burden in omentum (H) and ascites (I) at 30 d after transplantation of ID8-Luc or ID8-A11 cells. Data are represented as mean ± SEM of n = 6 (ID8) or n = 5 (ID8-A11), and statistically significant difference was calculated using Mann-Whitney U test; **, P < 0.01. All data are representative of two independent experiments.

**Figure 8.**
**CD163⁺ Tim4⁺ tissue-resident macrophages promote the CSC-like phenotype of ovarian cancer cells.** **(A)** Specific depletion of CD163⁺ Tim4⁺ (P4) macrophages using dxr-loaded αCD163-LNPs (αCD163-dxr); mice were injected i.p. with 1 mg/kg αCD163-dxr or controls (empty αCD163-LNPs or PBS) on days 1, 3, and 5, before injection of ID8-Luc cells on day 8. **(B and C)** Flow cytometry analysis of CD163^hi Lyve-1⁺ macrophages in omentum at 10 wk after prophylactic treatment with αCD163-dxr. Data are represented as mean ± SEM of n = 5 (PBS, αCD163-LNP) or n = 6 (αCD163-dxr), and statistically significant difference was calculated using Kruskal-Wallis one-way ANOVA followed by Dunn’s multiple comparisons test; *, P < 0.05; **, P < 0.01. **(D–F)** Omentum weight (D), total tumor cells in ascites (E), and ascites volume (F) at 10 wk after prophylactic treatment with αCD163-dxr. **(G)** Ex vivo bioluminescence analysis of metastases on the diaphragm. Data are represented as mean ± SEM of n = 8, and statistically significant difference was calculated using Kruskal-Wallis one-way ANOVA followed by Dunn’s multiple comparisons test; *, P < 0.05; **, P < 0.01. **(H)** tSNE map of concatenated fcs files from flow cytometry analysis of tumor cells from ascites after prophylactic treatment with αCD163-dxr. tSNE parameters were computed on expression levels of CSC markers (CD44, CD54, CD55, CD106, CD117, CD140a, and EpCam), and individual sample files were color-coded according to treatment group (PBS, blue; αCD163-ctl, red; αCD163-dxr, green; n = 8). This analysis identified distinct clusters from control-treated mice (PBS or αCD163-LNP; C1, black) and αCD163-dxr–treated mice (C2, gray). Expression of the individual CSC markers was subsequently visualized by heatmap statistics in a tSNE map of the concatenated samples within C1 (PBS or αCD163-LNP) and C2 (αCD163-dxr; right). **(I)** Flow cytometry analysis identifying the proportion of malignant cells expressing specific CSC markers: CD54, CD55, CD106, and CD117. See Fig. S5 G for the gating strategy. Data are represented as mean ± SEM of n = 8, and statistically significant difference was calculated using Kruskal-Wallis one-way ANOVA followed by Dunn’s multiple comparisons test; **, P < 0.01. **(J)** Gene expression analysis of Gata3, Stat3, Wnt5a, and Mertk in tumor cells from omentum after specific depletion of CD163⁺ Tim4⁺ (P1) macrophages, as described in A. dCT, delta cycle threshold. Data are represented as mean ± SEM of n = 6, and statistically significant difference was calculated using Kruskal-Wallis one-way ANOVA followed by Dunn’s multiple comparisons test; *, P < 0.05; **, P < 0.01. A–G are representative of three independent experiments, whereas H–J are representative of two independent experiments.

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Comment in

The omentum, a niche for premetastatic ovarian cancer.
Ma X. Ma X. J Exp Med. 2020 Apr 6;217(4):e20192312. doi: 10.1084/jem.20192312. J Exp Med. 2020. PMID: 32103261 Free PMC article.

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[1] Abubaker K., Luwor R.B., Zhu H., McNally O., Quinn M.A., Burns C.J., Thompson E.W., Findlay J.K., and Ahmed N.. 2014. Inhibition of the JAK2/STAT3 pathway in ovarian cancer results in the loss of cancer stem cell-like characteristics and a reduced tumor burden. BMC Cancer. 14:317 10.1186/1471-2407-14-317 - DOI - PMC - PubMed

[2] Abubaker K., Luwor R.B., Zhu H., McNally O., Quinn M.A., Burns C.J., Thompson E.W., Findlay J.K., and Ahmed N.. 2014. Inhibition of the JAK2/STAT3 pathway in ovarian cancer results in the loss of cancer stem cell-like characteristics and a reduced tumor burden. BMC Cancer. 14:317 10.1186/1471-2407-14-317 - DOI - PMC - PubMed

[3] AlHossiny M., Luo L., Frazier W.R., Steiner N., Gusev Y., Kallakury B., Glasgow E., Creswell K., Madhavan S., Kumar R., and Upadhyay G.. 2016. Ly6E/K signaling to TGFβ promotes breast cancer progression, immune escape, and drug resistance. Cancer Res. 76:3376–3386. 10.1158/0008-5472.CAN-15-2654 - DOI - PMC - PubMed

[4] AlHossiny M., Luo L., Frazier W.R., Steiner N., Gusev Y., Kallakury B., Glasgow E., Creswell K., Madhavan S., Kumar R., and Upadhyay G.. 2016. Ly6E/K signaling to TGFβ promotes breast cancer progression, immune escape, and drug resistance. Cancer Res. 76:3376–3386. 10.1158/0008-5472.CAN-15-2654 - DOI - PMC - PubMed

[5] Bapat S.A., Mali A.M., Koppikar C.B., and Kurrey N.K.. 2005. Stem and progenitor-like cells contribute to the aggressive behavior of human epithelial ovarian cancer. Cancer Res. 65:3025–3029. 10.1158/0008-5472.CAN-04-3931 - DOI - PubMed

[6] Bapat S.A., Mali A.M., Koppikar C.B., and Kurrey N.K.. 2005. Stem and progenitor-like cells contribute to the aggressive behavior of human epithelial ovarian cancer. Cancer Res. 65:3025–3029. 10.1158/0008-5472.CAN-04-3931 - DOI - PubMed

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Tissue-resident macrophages in omentum promote metastatic spread of ovarian cancer

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Tissue-resident macrophages in omentum promote metastatic spread of ovarian cancer

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