Obesity is associated with chronic, low-grade inflammation, which can disrupt homeostasis within tissue microenvironments. Given the correlation between obesity and relative risk of death from cancer, we investigated whether obesity-associated inflammation promotes metastatic progression. We demonstrate that obesity causes lung neutrophilia in otherwise normal mice, which is further exacerbated by the presence of a primary tumour. The increase in lung neutrophils translates to increased breast cancer metastasis to this site, in a GM-CSF- and IL5-dependent manner. Importantly, weight loss is sufficient to reverse this effect, and reduce serum levels of GM-CSF and IL5 in both mouse models and humans. Our data indicate that special consideration of the obese patient population is critical for effective management of cancer progression.
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We thank members of the Joyce and Dannenberg laboratories and V. Mittal for insightful comments and discussion. We acknowledge J. O. Alemán for assistance in providing human sera from weight loss trials. We thank H.-W. Wang for originally isolating the PyMT-BL6 cell lines used herein, and F. Klemm and J. Kowal for critically reading the manuscript. This research was supported by the Breast Cancer Research Foundation (J.A.J., A.J.D.), the Ludwig Institute for Cancer Research (J.A.J.), NIH/NCI U54 CA210184-01 (A.J.D.), the Botwinick-Wolfensohn Foundation (in memory of Mr and Mrs Benjamin Botwinick) (A.J.D.), the Sackler Center for Biomedicine and Nutrition Research at The Rockefeller University (P.R.H.), a National Cancer Institute Cancer Center Support Grant awarded to MSKCC (P30 CA008748), and fellowships from the Canadian Institutes of Health Research (D.F.Q., L.A.W.), National Cancer Institute F31CA171384 (O.C.O.), and the American Brain Tumor Association in honour of Joel A. Gingras (L.A.).
The authors declare no competing financial interests.
Integrated supplementary information
(a) Gating strategy for flow cytometry of CD11b+Gr1+ cells throughout this study, demonstrating that the Gr1+ cells are Ly6CloLy6G+ neutrophils. CD11b+Gr1+ populations are shown as a red overlay upon total CD11b+ cells, graphed on Ly6C (x-axis) by Ly6G (y-axis) staining intensity dot plots. (b) Giemsa stain for FACS-purified CD11b+Gr1+ cells, representing banded and hyper-segmented neutrophils (left), with a smaller subset showing a myelocyte precursor morphology (right). Scale bar = 10 μm. (c) Flow cytometry analysis of total CD45+CD3+ T cells, CD45+CD3+CD4+ helper T cells, and CD45+CD3+CD8+ cytotoxic T cells in the lungs of mice from the diet-induced obesity (DIO) model. n = 4 mice; mean ± s.e.m., 2-tailed unpaired Student’s t-test. (d) Flow cytometry analysis comparing myeloid cell populations in lung, liver and brain in the context of the DIO model. n = 4 mice, matched for each organ presented; mean ± s.e.m., 2-tailed unpaired Student’s t-test. (e) Flow cytometry analysis comparing myeloid cell populations in liver in wild-type (WT) and ob/ob mice. n = 10 mice; mean ± s.e.m., 2-tailed unpaired Student’s t-test. (f) Schematic representation of diet-switch trial. 4 week-old female WT BL6 mice were enrolled on high fat (HF) diet for 15 w, followed by a switch to low fat (LF) diet for an additional 7w.
Supplementary Figure 2 Development and characterization of an immune competent model of breast cancer in the BL6 genetic background.
(a) Cell lines were isolated from MMTV-PyMT mice backcrossed into a BL6 background and tested for their capacity to grow in vivo in WT BL6 animals. Graph shows primary tumor volume over time, measured by calipers biweekly (beginning at 19 d-post injection, when tumors were first palpable), after injecting a panel of seven PyMT-BL6 cell lines into the mammary fat pad of WT BL6 mice (700,000 cells/mouse). n = 5 mice per group; mean ± s.e.m. Three cell lines were selected from this panel for further use in the study: 99LN, 86R2, and 91R2. (b) qRT–PCR analysis of hormone receptor status, and epithelial versus mesenchymal cell marker expression in 99LN, 86R2 and 91R2 cell lines. n = 4 passages per line; mean ± s.e.m. (c) In vitro migration (left) and invasion (right) assays through a Transwell chamber, comparing baseline capacity for metastatic phenotypes in 99LN, 86R2 and 91R2 cell lines. FOV: field of view. n = 20 chambers/group; mean ± s.e.m. Kruskal-Wallis test and Dunn’s multiple comparisons test. (d) H&E image of lung showing spontaneous metastases arising from 99LN primary tumors after ∼2 months. Scale bar = 1,000 μm. (e) Primary tumor volume measured every 10 d over 60 d for 86R2 cells (LF, n = 5 mice; HF, n = 4 mice; mean ± s.e.m., 2-tailed unpaired Student’s t-test) or 99LN cells (LF, n = 10 mice; HF, n = 9 mice; mean ± s.e.m., 2-tailed unpaired Student’s t-test) injected into the mammary fat pad, in the context of the diet-induced obesity (DIO) model (1.5 × 106 cells/mouse). LF: low fat, HF: high fat. (f) Representative H&E image of lungs with spontaneous micro-metastases (black arrows) arising from 99LN mammary fat pad tumors implanted in LF or HF mice after ∼2 months. n = 5 mice/group corresponding to Fig. 2e. Scale bar = 500 μm.
Supplementary Figure 3 The lung neutrophilia and metastasis phenotype from the DIO model is recapitulated in ob/ob mice.
(a) Bioluminescent imaging (BLI) 48 h post-injection of 99LN breast cancer cells into the tail vein of WT or ob/ob animals. Quantification (left) and representative images (right) are presented, showing elevated metastasis in the ob/ob setting. (b) Flow cytometric analysis of lung neutrophils (CD45+CD11b+Ly6CloLy6G+) from trial presented in a. (c) qRT–PCR analysis of Cxcr2, Cxcr4, S100a8, and S100a9 gene expression in FACS-purified neutrophils from lungs of WT or ob/ob mice. For (a–c), n = 5 mice/group; mean ± s.e.m., 2-tailed unpaired Student’s t-test. (d) CFSE assay to assess suppressive activity of LF or HF neutrophils on CD8+ cytotoxic T cells. T cell proliferation was assessed by dilution of CFSE dye (that is, each division results in reduced brightness). Cells were isolated by FACS from n = 6 mice, one representative histogram is shown; all replicates showed no changes between LF and HF groups. (e) Flow cytometry gating strategy for NK cell cytotoxicity assay corresponding to (f). (f) Flow cytometry analysis of the degranulation marker CD107a on NK1.1+ cells after in vitro co-culture with neutrophils isolated from LF or HF peripheral blood. Cells were isolated by FACS from n = 6 mice/group; mean ± s.e.m., one-way ANOVA and Bonferroni’s multiple comparisons test. (g) Flow cytometry analysis of peripheral NK cell cytotoxicity in tumor-bearing mice from the DIO model, as quantified by percent of CD107a+ cells of total NK1.1+ cells in blood. Data are shown as Tukey’s box and whisker plots. All data points were included in statistical analyses, Mann-Whitney test (non-significant), n = 6 mice/group. Box plots represent median and interquartile range while whiskers represent maximum and minimum values excluding outliers. Each symbol represents one mouse.
(a) Schematic representation of Gr1 neutralization trial in the context of the DIO model and experimental metastasis, as shown in Fig. 3h–i. (b) Validation in non-tumor bearing animals that Gr1 antibody-mediated neutralization is effective at depleting target cells over three days in blood, spleen, and lung. (c) Flow cytometry quantification of CD11b+Ly6G+ cells (left) and CD11b+Ly6C+ cells (right) in blood from the anti-Gr1 neutralization trial. LF, n = 5 mice; HF + IgG, n = 9 mice; HF + αGr1, n = 8 mice; mix-max boxplot, all data points shown, one-way ANOVA and Dunnett’s multiple comparisons test. Box plots represent median and interquartile range while whiskers represent maximum and minimum values excluding outliers. Each symbol represents one mouse.
(a) Cross-species cytokine array heatmap showing log2(fold) changes of species-concordant factors that were significantly different between obese mouse (Mu) and human (Hu) serum, versus lean Mu and Hu serum. Red indicates factors that were upregulated in obese serum, and blue indicates factors that were downregulated in obese serum. For a full list of factors and data quantification, see Supplementary Table 2. (b) Quantification of log2(fold) and P-values for cytokine array results as shown in a. (c) ELISA analysis of serum GM-CSF or (d) IL5 in lean and obese human donors. n = 10 donors/group; mean ± s.d., Mann-Whitney test. (e–k) qRT–PCR analysis of mRNA levels for 8 candidate factors identified from cytokine array across different bulk tissues from n = 4 HF-fed mice; mean ± s.e.m.
Supplementary Figure 6 Effect of recombinant GM-CSF treatment on myeloid cell subsets in spleen and bone marrow.
(a) Flow cytometry analysis of CD11b+Gr1+ cells in spleen or (b) bone marrow in WT BL6 animals treated for 5 consecutive days with rGM-CSF versus a PBS control, as shown in Fig. 5a. n = 5 mice/group; mean ± s.e.m., 2-tailed unpaired Student’s t-test. Box plots represent median and interquartile range while whiskers represent maximum and minimum values excluding outliers. Each symbol represents one mouse.
(a) Representative flow cytometry plots (left) and quantification (right) of lung CD3+ T cells in WT BL6 animals after treatment with rIL5, in the trial as shown in Fig. 6b. n = 5 mice/group; mean ± s.e.m., 2-tailed unpaired Student’s t-test. (b) Trial design for rIL5 +/- anti-GM-CSF experiment in WT BL6 mice. Briefly, WT mice were treated for 5 consecutive days with rIL5 prior to tail vein injection with 99LN breast cancer cells at t = 0 d (48 h metastasis assay). At −3 d and −1 d, mice were also treated with a neutralizing antibody against GM-CSF. Mice were treated continually with rmIL5 for the duration of the 48 h metastasis trial. (c) Bioluminescent imaging (BLI) after tail vein injection with breast cancer cells for the trial shown in b. Quantification of photons/second (left) and representative images (right) are presented. n = 10 mice/group; Tukey boxplot, one-way ANOVA and Bonferroni’s multiple comparisons test. (d) Flow cytometry analysis of lung neutrophils from the trial shown in b. n = 5 mice/group from the full trial in b were used for flow analysis; Tukey boxplot, one-way ANOVA and Bonferroni’s multiple comparisons test. (e) Flow cytometry analysis of CD45+CD11b+Ly6CloLy6G+ lung neutrophils in athymic/nude or NOD-scid Il2rgnull (NSG) mice after treatment with either PBS or rIL5 for 5 consecutive days. n = 5 mice/group; mean ± s.e.m., 2-tailed unpaired Student’s t test. (f) Flow cytometry comparison of lung IL5ra + neutrophils, eosinophils, or monocytes in BL6 (n = 5 mice/group), NSG (n = 10 mice/group), or nude mice (n = 10 mice/group). Data are presented as mean ± s.e.m. Box plots represent median and interquartile range while whiskers represent maximum and minimum values excluding outliers. Each symbol represents one mouse.
Supplementary Figure 8 Neutrophil turnover occurs at 8 h post-adoptive cell transfer in WT and ob/ob mice.
(a) Flow cytometry analysis of neutrophil numbers (events per million, y-axis × 103) at 4 h and 8 h post-adoptive transfer, showing that neutrophils turnover by 8 h across all groups. n = 5 mice/recipient group; mean ± s.e.m displayed. (b) Flow cytometry analysis of fluorescently labeled circulating neutrophils 8 h post-adoptive transfer, demonstrating relatively equal representation of both red (ob/ob donor) and green (WT donor) cells. n = 5 mice/recipient group; mean ± s.e.m displayed.
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Quail, D., Olson, O., Bhardwaj, P. et al. Obesity alters the lung myeloid cell landscape to enhance breast cancer metastasis through IL5 and GM-CSF. Nat Cell Biol 19, 974–987 (2017). https://doi.org/10.1038/ncb3578
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