Macrophage-secreted interleukin-35 regulates cancer cell plasticity to facilitate metastatic colonization

C.-C. Lee, J.-C. Lin, W.-L. Hwang, Y.-J. Kuo, H.-K. Chen, S.-K. Tai, C.-C. Lin, M.-H. Yang

Research output: Contribution to journalArticle

16 Citations (Scopus)

Abstract

A favorable interplay between cancer cells and the tumor microenvironment (TME) facilitates the outgrowth of metastatic tumors. Because of the distinct initiating processes between primary and metastatic tumors, we investigate the differences in tumor-associated macrophages (TAMs) from primary and metastatic cancers. Here we show that dual expression of M1 and M2 markers is noted in TAMs from primary tumors, whereas predominant expression of M2 markers is shown in metastatic TAMs. At metastatic sites, TAMs secrete interleukin-35 (IL-35) to facilitate metastatic colonization through activation of JAK2–STAT6-GATA3 signaling to reverse epithelial–mesenchymal transition (EMT) in cancer cells. In primary tumors, inflammation-induced EMT upregulates IL12Rβ2, a subunit of the IL-35 receptor, in cancer cells to help them respond to IL-35 during metastasis. Neutralization of IL-35 or knockout of IL-35 in macrophages reduces metastatic colonization. These results indicate the distinct TMEs of primary and metastatic tumors and provide potential targets for intercepting metastasis. © 2018, The Author(s).
Original languageEnglish
JournalNature Communications
Volume9
Issue number1
DOIs
Publication statusPublished - 2018
Externally publishedYes

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interleukins
macrophages
Macrophages
Interleukins
plastic properties
Plasticity
Tumors
tumors
cancer
Cells
Neoplasms
metastasis
markers
Cell Plasticity
Interleukin Receptors
Neoplasm Metastasis
Cellular Microenvironment
Tumor Microenvironment
Chemical activation
activation

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Macrophage-secreted interleukin-35 regulates cancer cell plasticity to facilitate metastatic colonization. / Lee, C.-C.; Lin, J.-C.; Hwang, W.-L.; Kuo, Y.-J.; Chen, H.-K.; Tai, S.-K.; Lin, C.-C.; Yang, M.-H.

In: Nature Communications, Vol. 9, No. 1, 2018.

Research output: Contribution to journalArticle

Lee, C.-C. ; Lin, J.-C. ; Hwang, W.-L. ; Kuo, Y.-J. ; Chen, H.-K. ; Tai, S.-K. ; Lin, C.-C. ; Yang, M.-H. / Macrophage-secreted interleukin-35 regulates cancer cell plasticity to facilitate metastatic colonization. In: Nature Communications. 2018 ; Vol. 9, No. 1.
@article{9c2e536e5a7045108899e9f99918ed3e,
title = "Macrophage-secreted interleukin-35 regulates cancer cell plasticity to facilitate metastatic colonization",
abstract = "A favorable interplay between cancer cells and the tumor microenvironment (TME) facilitates the outgrowth of metastatic tumors. Because of the distinct initiating processes between primary and metastatic tumors, we investigate the differences in tumor-associated macrophages (TAMs) from primary and metastatic cancers. Here we show that dual expression of M1 and M2 markers is noted in TAMs from primary tumors, whereas predominant expression of M2 markers is shown in metastatic TAMs. At metastatic sites, TAMs secrete interleukin-35 (IL-35) to facilitate metastatic colonization through activation of JAK2–STAT6-GATA3 signaling to reverse epithelial–mesenchymal transition (EMT) in cancer cells. In primary tumors, inflammation-induced EMT upregulates IL12Rβ2, a subunit of the IL-35 receptor, in cancer cells to help them respond to IL-35 during metastasis. Neutralization of IL-35 or knockout of IL-35 in macrophages reduces metastatic colonization. These results indicate the distinct TMEs of primary and metastatic tumors and provide potential targets for intercepting metastasis. {\circledC} 2018, The Author(s).",
author = "C.-C. Lee and J.-C. Lin and W.-L. Hwang and Y.-J. Kuo and H.-K. Chen and S.-K. Tai and C.-C. Lin and M.-H. Yang",
note = "Export Date: 9 October 2018 通訊地址: Yang, M.-H.; Taiwan International Graduate Program in Molecular Medicine, National Yang-Ming University and Academia SinicaTaiwan; 電子郵件: mhyang2@vghtpe.gov.tw 參考文獻: Acloque, H., Adams, M.S., Fishwick, K., Bronner-Fraser, M., Nieto, M.A., Epithelial–mesenchymal transitions: the importance of changing cell state in development and disease (2009) J. Clin. Invest., 119, pp. 1438-1449. , PID: 19487820; De Craene, B., Berx, G., Regulatory networks defining EMT during cancer initiation and progression (2013) Nat. Rev. Cancer, 13, pp. 97-110. , PID: 23344542; Mani, S.A., The epithelial–mesenchymal transition generates cells with properties of stem cells (2008) Cell, 133, pp. 704-715. , PID: 18485877; Yang, M.H., Bmi1 is essential in Twist1-induced epithelial–mesenchymal transition (2010) Nat. Cell Biol., 12, pp. 982-992. , PID: 20818389; Yu, M., Ex vivo culture of circulating breast tumor cells for individualized testing of drug susceptibility (2014) Science, 345, pp. 216-220. , PID: 25013076; Labelle, M., Begum, S., Hynes, R.O., Direct signaling between platelets and cancer cells induces an epithelial–mesenchymal-like transition and promotes metastasis (2011) Cancer Cell., 20, pp. 576-590. , PID: 22094253; Li, R., A mesenchymal-to-epithelial transition initiates and is required for the nuclear reprogramming of mouse fibroblasts (2010) Cell Stem Cell, 7, pp. 51-63. , PID: 20621050; Samavarchi-Tehrani, P., Functional genomics reveals a BMP-driven mesenchymal-to-epithelial transition in the initiation of somatic cell reprogramming (2010) Cell Stem Cell, 7, pp. 64-77. , PID: 20621051; Celia-Terrassa, T., Epithelial–mesenchymal transition can suppress major attributes of human epithelial tumor-initiating cells (2012) J. Clin. Invest., 122, pp. 1849-1868. , PID: 22505459; Tsai, J.H., Donaher, J.L., Murphy, D.A., Chau, S., Yang, J., Spatiotemporal regulation of epithelial–mesenchymal transition is essential for squamous cell carcinoma metastasis (2012) Cancer Cell., 22, pp. 725-736. , PID: 23201165; Del Pozo Martin, Y., Mesenchymal cancer cell-stroma crosstalk promotes niche activation, epithelial reversion, and metastatic colonization (2015) Cell Rep., 13, pp. 1-14; Gao, D., Myeloid progenitor cells in the premetastatic lung promote metastases by inducing mesenchymal to epithelial transition (2012) Cancer Res., 72, pp. 1384-1394. , PID: 22282653; Massagu{\'e}, J., Obenauf, A.C., Metastatic colonization by circulating tumour cells (2016) Nature, 529, pp. 298-306. , PID: 26791720; Noy, R., Pollard, J.W., Tumor-associated macrophages: from mechanisms to therapy (2014) Immunity, 41, pp. 49-61. , PID: 25035953; Biswas, S.K., Mantovani, A., Macrophage plasticity and interaction with lymphocyte subsets: cancer as a paradigm (2010) Nat. Immunol., 11, pp. 889-896. , PID: 20856220; Ma, J., The M1 form of tumor-associated macrophages in non-small cell lung cancer is positively associated with survival time (2010) BMC Cancer, 10. , PID: 20338029; Ong, S.M., Macrophages in human colorectal cancer are pro-inflammatory and prime T cells towards an anti-tumour type-1 inflammatory response (2011) Eur. J. Immunol., 42, pp. 89-100. , PID: 22009685; Qian, B.Z., A distinct macrophage population mediates metastatic breast cancer cell extravasation, establishment and growth (2009) PLoS ONE, 4. , PID: 19668347; Qian, B.Z., CCL2 recruits inflammatory monocytes to facilitate breast-tumour metastasis (2011) Nature, 475, pp. 222-225. , PID: 21654748; Pallasch, C.P., Sensitizing protective tumor microenvironments to antibody-mediated therapy (2014) Cell, 156, pp. 590-602. , PID: 24485462; Huang, R.L., ANGPTL4 modulates vascular junction integrity by integrin signaling and disruption of intercellular VE-cadherin and claudin-5 clusters (2011) Blood, 118, pp. 3990-4002. , PID: 21841165; Jordan, J.A., Role of IL-18 in acute lung inflammation (2001) J. Immunol., 167, pp. 7060-7068. , PID: 11739527; Nieto, M.A., Epithelial plasticity: a common theme in embryonic and cancer cells (2013) Science, 342, p. 1234850. , PID: 24202173; L{\'o}pez-Novoa, J.M., Nieto, M.A., Inflammation and EMT: an alliance towards organ fibrosis and cancer progression (2009) EMBO Mol. Med., 1, pp. 303-314. , PID: 20049734; Cohen, E.N., Inflammation mediated metastasis: immune induced epithelial-to-mesenchymal transition in inflammatory breast cancer cells (2015) PLoS ONE, 10. , PID: 26207636; Ricciardi, M., Epithelial-to-mesenchymal transition (EMT) induced by inflammatory priming elicits mesenchymal stromal cell-like immune-modulatory properties in cancer cells (2015) Br. J. Cancer, 112, pp. 1067-1075. , PID: 25668006; Yan, W., Cao, Q.J., Arenas, R.B., Bentley, B., Shao, R., GATA3 inhibits breast cancer metastasis through the reversal of epithelial–mesenchymal transition (2010) J. Biol. Chem., 285, pp. 14042-14051. , PID: 20189993; Kouros-Mehr, H., GATA-3 links tumor differ- entiation and dissemination in a luminal breast cancer model (2008) Cancer Cell, 13, pp. 141-152. , PID: 18242514; Yoon, N.K., Higher levels of GATA3 predict better survival in women with breast cancer (2010) Hum. Pathol., 41, pp. 1794-1801. , PID: 21078439; Kaplan, M.H., Schindler, U., Smiley, S.T., Grusby, M.J., Stat6 is required for mediating responses to IL-4 and for the development of Th2 cells (1996) Immunity, 4, pp. 313-319. , PID: 8624821; Zheng, W.P., Flavell, R.A., The transcription factor GATA-3 is necessary and sufficient for Th2 cytokine gene expression in CD4 T cells (1997) Cell, 89, pp. 587-596. , PID: 9160750; La Flamme, A.C., Type II-activated murine macrophages produce IL-4 (2012) PLoS ONE, 7. , PID: 23071691; Zheng, X.F., Lipopolysaccharide-induced M2 to M1 macrophage transformation for IL-12p70 production is blocked by candida albicans mediated upregulation of EBI3 expression (2013) PLoS ONE, 8. , PID: 23724011; Venmar, K.T., IL4 receptor ILR4α regulates metastatic colonization by mammary tumors through multiple signaling pathways (2014) Cancer Res., 74, pp. 4329-4340. , PID: 24947041; Collison, L.W., The composition and signaling of the IL-35 receptor are unconventional (2012) Nat. Immunol., 13, pp. 290-299. , PID: 22306691; Collison, L.W., Vignali, D.A., Interleukin-35: odd one out or part of the family? (2008) Immunol. Rev., 226, pp. 248-262. , PID: 19161429; Collison, L.W., The inhibitory cytokine IL-35 contributes to regulatory T-cell function (2007) Nature, 450, pp. 566-569. , PID: 18033300; Olson, B.M., Sullivan, J., Burlingham, W., Interleukin 35: a key mediator of suppression and the propagation of infectious tolerance (2013) Front. Immunol., 4, p. 315. , PID: 24151492; Turnis, M.E., Interleukin-35 limits anti-tumor immunity (2016) Immunity, 44, pp. 316-329. , PID: 26872697; Long, J., IL-35 expression in hepatocellular carcinoma cells is associated with tumor progression (2016) Oncotarget, 7, pp. 45678-45686. , PID: 27329841; Huang, C., Tumour-derived Interleukin 35 promotes pancreatic ductal adenocarcinoma cell extravasation and metastasis by inducing ICAM1 expression (2017) Nat. Commun., 8. , PID: 28102193; Wu, Y., Zhou, B.P., TNF-α/NF-κB/Snail pathway in cancer cell migration and invasion (2010) Br. J. Cancer, 102, p. 639. , PID: 20087353; Li, C.W., Epithelial–mesenchymal transition induced by TNF-α requires NF-κB–mediated transcriptional upregulation of Twist1 (2012) Cancer Res., 72, pp. 1290-1300. , PID: 22253230; Si, W., Dysfunction of the reciprocal feedback loop between GATA3-and ZEB2-nucleated repression programs contributes to breast cancer metastasis (2015) Cancer Cell., 27, pp. 822-836. , PID: 26028330; Taube, J.H., Core epithelial-to-mesenchymal transition interactome gene-expression signature is associated with claudin-low and metaplastic breast cancer subtypes (2010) Proc. Natl Acad. Sci. USA, 107, pp. 15449-15454. , PID: 20713713; Martinez, F.O., Gordon, S., Locati, M., Mantovani, A., Transcriptional profiling of the human monocyte-to-macrophage differentiation and polarization: new molecules and patterns of gene expression (2006) J. Immunol., 177, pp. 7303-7311. , PID: 17082649; Kzhyshkowska, J., Alternatively activated macrophages regulate extracellular levels of the hormone placental lactogen via receptor-mediated uptake and transcytosis (2008) J. Immunol., 180, pp. 3028-3037. , PID: 18292525; Park, S.Y., Stabilin-1 mediates phosphatidylserine-dependent clearance of cell corpses in alternatively activated macrophages (2009) J. Cell Sci., 122, pp. 3365-3373. , PID: 19726632",
year = "2018",
doi = "10.1038/s41467-018-06268-0",
language = "English",
volume = "9",
journal = "Nature Communications",
issn = "2041-1723",
publisher = "Nature Publishing Group",
number = "1",

}

TY - JOUR

T1 - Macrophage-secreted interleukin-35 regulates cancer cell plasticity to facilitate metastatic colonization

AU - Lee, C.-C.

AU - Lin, J.-C.

AU - Hwang, W.-L.

AU - Kuo, Y.-J.

AU - Chen, H.-K.

AU - Tai, S.-K.

AU - Lin, C.-C.

AU - Yang, M.-H.

N1 - Export Date: 9 October 2018 通訊地址: Yang, M.-H.; Taiwan International Graduate Program in Molecular Medicine, National Yang-Ming University and Academia SinicaTaiwan; 電子郵件: mhyang2@vghtpe.gov.tw 參考文獻: Acloque, H., Adams, M.S., Fishwick, K., Bronner-Fraser, M., Nieto, M.A., Epithelial–mesenchymal transitions: the importance of changing cell state in development and disease (2009) J. Clin. Invest., 119, pp. 1438-1449. , PID: 19487820; De Craene, B., Berx, G., Regulatory networks defining EMT during cancer initiation and progression (2013) Nat. Rev. Cancer, 13, pp. 97-110. , PID: 23344542; Mani, S.A., The epithelial–mesenchymal transition generates cells with properties of stem cells (2008) Cell, 133, pp. 704-715. , PID: 18485877; Yang, M.H., Bmi1 is essential in Twist1-induced epithelial–mesenchymal transition (2010) Nat. Cell Biol., 12, pp. 982-992. , PID: 20818389; Yu, M., Ex vivo culture of circulating breast tumor cells for individualized testing of drug susceptibility (2014) Science, 345, pp. 216-220. , PID: 25013076; Labelle, M., Begum, S., Hynes, R.O., Direct signaling between platelets and cancer cells induces an epithelial–mesenchymal-like transition and promotes metastasis (2011) Cancer Cell., 20, pp. 576-590. , PID: 22094253; Li, R., A mesenchymal-to-epithelial transition initiates and is required for the nuclear reprogramming of mouse fibroblasts (2010) Cell Stem Cell, 7, pp. 51-63. , PID: 20621050; Samavarchi-Tehrani, P., Functional genomics reveals a BMP-driven mesenchymal-to-epithelial transition in the initiation of somatic cell reprogramming (2010) Cell Stem Cell, 7, pp. 64-77. , PID: 20621051; Celia-Terrassa, T., Epithelial–mesenchymal transition can suppress major attributes of human epithelial tumor-initiating cells (2012) J. Clin. Invest., 122, pp. 1849-1868. , PID: 22505459; Tsai, J.H., Donaher, J.L., Murphy, D.A., Chau, S., Yang, J., Spatiotemporal regulation of epithelial–mesenchymal transition is essential for squamous cell carcinoma metastasis (2012) Cancer Cell., 22, pp. 725-736. , PID: 23201165; Del Pozo Martin, Y., Mesenchymal cancer cell-stroma crosstalk promotes niche activation, epithelial reversion, and metastatic colonization (2015) Cell Rep., 13, pp. 1-14; Gao, D., Myeloid progenitor cells in the premetastatic lung promote metastases by inducing mesenchymal to epithelial transition (2012) Cancer Res., 72, pp. 1384-1394. , PID: 22282653; Massagué, J., Obenauf, A.C., Metastatic colonization by circulating tumour cells (2016) Nature, 529, pp. 298-306. , PID: 26791720; Noy, R., Pollard, J.W., Tumor-associated macrophages: from mechanisms to therapy (2014) Immunity, 41, pp. 49-61. , PID: 25035953; Biswas, S.K., Mantovani, A., Macrophage plasticity and interaction with lymphocyte subsets: cancer as a paradigm (2010) Nat. Immunol., 11, pp. 889-896. , PID: 20856220; Ma, J., The M1 form of tumor-associated macrophages in non-small cell lung cancer is positively associated with survival time (2010) BMC Cancer, 10. , PID: 20338029; Ong, S.M., Macrophages in human colorectal cancer are pro-inflammatory and prime T cells towards an anti-tumour type-1 inflammatory response (2011) Eur. J. Immunol., 42, pp. 89-100. , PID: 22009685; Qian, B.Z., A distinct macrophage population mediates metastatic breast cancer cell extravasation, establishment and growth (2009) PLoS ONE, 4. , PID: 19668347; Qian, B.Z., CCL2 recruits inflammatory monocytes to facilitate breast-tumour metastasis (2011) Nature, 475, pp. 222-225. , PID: 21654748; Pallasch, C.P., Sensitizing protective tumor microenvironments to antibody-mediated therapy (2014) Cell, 156, pp. 590-602. , PID: 24485462; Huang, R.L., ANGPTL4 modulates vascular junction integrity by integrin signaling and disruption of intercellular VE-cadherin and claudin-5 clusters (2011) Blood, 118, pp. 3990-4002. , PID: 21841165; Jordan, J.A., Role of IL-18 in acute lung inflammation (2001) J. Immunol., 167, pp. 7060-7068. , PID: 11739527; Nieto, M.A., Epithelial plasticity: a common theme in embryonic and cancer cells (2013) Science, 342, p. 1234850. , PID: 24202173; López-Novoa, J.M., Nieto, M.A., Inflammation and EMT: an alliance towards organ fibrosis and cancer progression (2009) EMBO Mol. Med., 1, pp. 303-314. , PID: 20049734; Cohen, E.N., Inflammation mediated metastasis: immune induced epithelial-to-mesenchymal transition in inflammatory breast cancer cells (2015) PLoS ONE, 10. , PID: 26207636; Ricciardi, M., Epithelial-to-mesenchymal transition (EMT) induced by inflammatory priming elicits mesenchymal stromal cell-like immune-modulatory properties in cancer cells (2015) Br. J. Cancer, 112, pp. 1067-1075. , PID: 25668006; Yan, W., Cao, Q.J., Arenas, R.B., Bentley, B., Shao, R., GATA3 inhibits breast cancer metastasis through the reversal of epithelial–mesenchymal transition (2010) J. Biol. Chem., 285, pp. 14042-14051. , PID: 20189993; Kouros-Mehr, H., GATA-3 links tumor differ- entiation and dissemination in a luminal breast cancer model (2008) Cancer Cell, 13, pp. 141-152. , PID: 18242514; Yoon, N.K., Higher levels of GATA3 predict better survival in women with breast cancer (2010) Hum. Pathol., 41, pp. 1794-1801. , PID: 21078439; Kaplan, M.H., Schindler, U., Smiley, S.T., Grusby, M.J., Stat6 is required for mediating responses to IL-4 and for the development of Th2 cells (1996) Immunity, 4, pp. 313-319. , PID: 8624821; Zheng, W.P., Flavell, R.A., The transcription factor GATA-3 is necessary and sufficient for Th2 cytokine gene expression in CD4 T cells (1997) Cell, 89, pp. 587-596. , PID: 9160750; La Flamme, A.C., Type II-activated murine macrophages produce IL-4 (2012) PLoS ONE, 7. , PID: 23071691; Zheng, X.F., Lipopolysaccharide-induced M2 to M1 macrophage transformation for IL-12p70 production is blocked by candida albicans mediated upregulation of EBI3 expression (2013) PLoS ONE, 8. , PID: 23724011; Venmar, K.T., IL4 receptor ILR4α regulates metastatic colonization by mammary tumors through multiple signaling pathways (2014) Cancer Res., 74, pp. 4329-4340. , PID: 24947041; Collison, L.W., The composition and signaling of the IL-35 receptor are unconventional (2012) Nat. Immunol., 13, pp. 290-299. , PID: 22306691; Collison, L.W., Vignali, D.A., Interleukin-35: odd one out or part of the family? (2008) Immunol. Rev., 226, pp. 248-262. , PID: 19161429; Collison, L.W., The inhibitory cytokine IL-35 contributes to regulatory T-cell function (2007) Nature, 450, pp. 566-569. , PID: 18033300; Olson, B.M., Sullivan, J., Burlingham, W., Interleukin 35: a key mediator of suppression and the propagation of infectious tolerance (2013) Front. Immunol., 4, p. 315. , PID: 24151492; Turnis, M.E., Interleukin-35 limits anti-tumor immunity (2016) Immunity, 44, pp. 316-329. , PID: 26872697; Long, J., IL-35 expression in hepatocellular carcinoma cells is associated with tumor progression (2016) Oncotarget, 7, pp. 45678-45686. , PID: 27329841; Huang, C., Tumour-derived Interleukin 35 promotes pancreatic ductal adenocarcinoma cell extravasation and metastasis by inducing ICAM1 expression (2017) Nat. Commun., 8. , PID: 28102193; Wu, Y., Zhou, B.P., TNF-α/NF-κB/Snail pathway in cancer cell migration and invasion (2010) Br. J. Cancer, 102, p. 639. , PID: 20087353; Li, C.W., Epithelial–mesenchymal transition induced by TNF-α requires NF-κB–mediated transcriptional upregulation of Twist1 (2012) Cancer Res., 72, pp. 1290-1300. , PID: 22253230; Si, W., Dysfunction of the reciprocal feedback loop between GATA3-and ZEB2-nucleated repression programs contributes to breast cancer metastasis (2015) Cancer Cell., 27, pp. 822-836. , PID: 26028330; Taube, J.H., Core epithelial-to-mesenchymal transition interactome gene-expression signature is associated with claudin-low and metaplastic breast cancer subtypes (2010) Proc. Natl Acad. Sci. USA, 107, pp. 15449-15454. , PID: 20713713; Martinez, F.O., Gordon, S., Locati, M., Mantovani, A., Transcriptional profiling of the human monocyte-to-macrophage differentiation and polarization: new molecules and patterns of gene expression (2006) J. Immunol., 177, pp. 7303-7311. , PID: 17082649; Kzhyshkowska, J., Alternatively activated macrophages regulate extracellular levels of the hormone placental lactogen via receptor-mediated uptake and transcytosis (2008) J. Immunol., 180, pp. 3028-3037. , PID: 18292525; Park, S.Y., Stabilin-1 mediates phosphatidylserine-dependent clearance of cell corpses in alternatively activated macrophages (2009) J. Cell Sci., 122, pp. 3365-3373. , PID: 19726632

PY - 2018

Y1 - 2018

N2 - A favorable interplay between cancer cells and the tumor microenvironment (TME) facilitates the outgrowth of metastatic tumors. Because of the distinct initiating processes between primary and metastatic tumors, we investigate the differences in tumor-associated macrophages (TAMs) from primary and metastatic cancers. Here we show that dual expression of M1 and M2 markers is noted in TAMs from primary tumors, whereas predominant expression of M2 markers is shown in metastatic TAMs. At metastatic sites, TAMs secrete interleukin-35 (IL-35) to facilitate metastatic colonization through activation of JAK2–STAT6-GATA3 signaling to reverse epithelial–mesenchymal transition (EMT) in cancer cells. In primary tumors, inflammation-induced EMT upregulates IL12Rβ2, a subunit of the IL-35 receptor, in cancer cells to help them respond to IL-35 during metastasis. Neutralization of IL-35 or knockout of IL-35 in macrophages reduces metastatic colonization. These results indicate the distinct TMEs of primary and metastatic tumors and provide potential targets for intercepting metastasis. © 2018, The Author(s).

AB - A favorable interplay between cancer cells and the tumor microenvironment (TME) facilitates the outgrowth of metastatic tumors. Because of the distinct initiating processes between primary and metastatic tumors, we investigate the differences in tumor-associated macrophages (TAMs) from primary and metastatic cancers. Here we show that dual expression of M1 and M2 markers is noted in TAMs from primary tumors, whereas predominant expression of M2 markers is shown in metastatic TAMs. At metastatic sites, TAMs secrete interleukin-35 (IL-35) to facilitate metastatic colonization through activation of JAK2–STAT6-GATA3 signaling to reverse epithelial–mesenchymal transition (EMT) in cancer cells. In primary tumors, inflammation-induced EMT upregulates IL12Rβ2, a subunit of the IL-35 receptor, in cancer cells to help them respond to IL-35 during metastasis. Neutralization of IL-35 or knockout of IL-35 in macrophages reduces metastatic colonization. These results indicate the distinct TMEs of primary and metastatic tumors and provide potential targets for intercepting metastasis. © 2018, The Author(s).

U2 - 10.1038/s41467-018-06268-0

DO - 10.1038/s41467-018-06268-0

M3 - Article

VL - 9

JO - Nature Communications

JF - Nature Communications

SN - 2041-1723

IS - 1

ER -