NF-κB regulates GDF-15 to suppress macrophage surveillance during early tumor development
Nivedita M. Ratnam, … , David J. Wang, Denis C. Guttridge
Nivedita M. Ratnam, … , David J. Wang, Denis C. Guttridge
Published September 11, 2017
Citation Information: J Clin Invest. 2017;127(10):3796-3809. https://doi.org/10.1172/JCI91561.
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Research Article Cell biology Immunology Article has an altmetric score of 50

NF-κB regulates GDF-15 to suppress macrophage surveillance during early tumor development

Abstract

Macrophages are attracted to developing tumors and can participate in immune surveillance to eliminate neoplastic cells. In response, neoplastic cells utilize NF-κB to suppress this killing activity, but the mechanisms underlying their self-protection remain unclear. Here, we report that this dynamic interaction between tumor cells and macrophages is integrally linked by a soluble factor identified as growth and differentiation factor 15 (GDF-15). In vitro, tumor-derived GDF-15 signals in macrophages to suppress their proapoptotic activity by inhibiting TNF and nitric oxide (NO) production. In vivo, depletion of GDF-15 in Ras-driven tumor xenografts and in an orthotopic model of pancreatic cancer delayed tumor development. This delay correlated with increased infiltrating antitumor macrophages. Further, production of GDF-15 is directly regulated by NF-κB, and the colocalization of activated NF-κB and GDF-15 in epithelial ducts of human pancreatic adenocarcinoma supports the importance of this observation. Mechanistically, we found that GDF-15 suppresses macrophage activity by inhibiting TGF-β–activated kinase (TAK1) signaling to NF-κB, thereby blocking synthesis of TNF and NO. Based on these results, we propose that the NF-κB/GDF-15 regulatory axis is important for tumor cells in evading macrophage immune surveillance during the early stages of tumorigenesis.

Authors

Nivedita M. Ratnam, Jennifer M. Peterson, Erin E. Talbert, Katherine J. Ladner, Priyani V. Rajasekera, Carl R. Schmidt, Mary E. Dillhoff, Benjamin J. Swanson, Ericka Haverick, Raleigh D. Kladney, Terence M. Williams, Gustavo W. Leone, David J. Wang, Denis C. Guttridge

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Figure 3

GDF-15 is required for development of KRas-induced PDAC.

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GDF-15 is required for development of KRas-induced PDAC. (A) KPC cells e...
(A) KPC cells expressing an shRNA against Gdf-15 were generated (2 clones, 1 and 4). Data are plotted as average gene expression (normalized to Gapdh) ± SEM. n = 3. *P ≤ 0.05, Student’s t test. (B) KPC control and KPC Gdf-15–knockdown cells (described above as clone 1) were injected orthotopically into the tail of the pancreas in C57BL/6 albino mice. Tumor growth was tracked by bioluminescence imaging. Shown are representative images tracking tumor growth of the mice. (C) The graph represents tumor growth derived from bioluminescence measured in B. n = 6 per cohort. Data are shown as mean ± SEM. *P ≤ 0.05, SPSS repeated measures, general linear model. (D) KPC control and KPC Gdf-15–knockdown cells (described above as clone 1) were injected orthotopically into the tail of the pancreas in C57BL/6 albino mice. The graph represents the average weight of tumors obtained from cohorts of 5 mice per condition similar to what is shown in Figure 2C. *P ≤ 0.05, Student’s t test. (E) Control and Gdf-15–knockdown orthotopic tumors were analyzed for H&E, CK19, and Ki67 colocalization and CC3. Original magnification, ×20. Scale bar: 15 μm. (F) CK19 (cytoplasmic, pink)/ Ki67 (nuclear, brown) dual staining was quantitated and graphed from 5 mice per condition from at least 5 fields of view of the tumor area per mouse. Data are shown as mean ± SEM. *P ≤ 0.05, Student’s t test. For CC3 staining, quantitation from staining signal was graphed as a ratio of the percentage of CC3+ cells to the percentage average of proliferating cells. Data are shown as mean ± SEM. Student’s t test, NS. (G) Kaplan-Meier curve assessing survival of C57BL/6 albino mice (n = 10 per cohort) injected with either KPC control or KPC Gdf-15–knockdown cells.