TY - JOUR
T1 - FLT1 signaling in metastasis-associated macrophages activates an inflammatory signature that promotes breast cancer metastasis
AU - Qian, Bin Zhi
AU - Zhang, Hui
AU - Li, Jiufeng
AU - He, Tianfang
AU - Yeo, Eun Jin
AU - Soong, Daniel Y.H.
AU - Carragher, Neil O.
AU - Munro, Alison
AU - Chang, Alvin
AU - Bresnick, Anne R.
AU - Lang, Richard A.
AU - Pollard, Jeffrey W.
N1 - Funding Information:
Research reported in this publication was supported by the National Cancer Institute of the National Institutes of Health under award numbers R01CA131270 and PO1CA100324 and the Wellcome Trust (101067/Z/13/Z) to J.W. Pollard and a CRUK Career Development Award (C49791/A17367) Fellowship to B.-Z. Qian. The authors declare no competing financial interests.
Publisher Copyright:
© 2015 Qian et al.
PY - 2015/8/24
Y1 - 2015/8/24
N2 - Although the link between inflammation and cancer initiation is well established, its role in metastatic diseases, the primary cause of cancer deaths, has been poorly explored. Our previous studies identified a population of metastasis-associated macrophages (MAMs) recruited to the lung that promote tumor cell seeding and growth. Here we show that FMS-like tyrosine kinase 1 (Flt1, also known as VEGFR1) labels a subset of macrophages in human breast cancers that are significantly enriched in metastatic sites. In mouse models of breast cancer pulmonary metastasis, MAMs uniquely express FLT1. Using several genetic models, we show that macrophage FLT1 signaling is critical for metastasis. FLT1 inhibition does not affect MAM recruitment to metastatic lesions but regulates a set of inflammatory response genes, including colony-stimulating factor 1 (CSF1), a central regulator of macrophage biology. Using a gain-of-function approach, we show that CSF1-mediated autocrine signaling in MAMs is downstream of FLT1 and can restore the tumor-promoting activity of FLT1-inhibited MAMs. Thus, CSF1 is epistatic to FLT1, establishing a link between FLT1 and inflammatory responses within breast tumor metastases. Importantly, FLT1 inhibition reduces tumor metastatic efficiency even after initial seeding, suggesting that these pathways represent therapeutic targets in metastatic disease.
AB - Although the link between inflammation and cancer initiation is well established, its role in metastatic diseases, the primary cause of cancer deaths, has been poorly explored. Our previous studies identified a population of metastasis-associated macrophages (MAMs) recruited to the lung that promote tumor cell seeding and growth. Here we show that FMS-like tyrosine kinase 1 (Flt1, also known as VEGFR1) labels a subset of macrophages in human breast cancers that are significantly enriched in metastatic sites. In mouse models of breast cancer pulmonary metastasis, MAMs uniquely express FLT1. Using several genetic models, we show that macrophage FLT1 signaling is critical for metastasis. FLT1 inhibition does not affect MAM recruitment to metastatic lesions but regulates a set of inflammatory response genes, including colony-stimulating factor 1 (CSF1), a central regulator of macrophage biology. Using a gain-of-function approach, we show that CSF1-mediated autocrine signaling in MAMs is downstream of FLT1 and can restore the tumor-promoting activity of FLT1-inhibited MAMs. Thus, CSF1 is epistatic to FLT1, establishing a link between FLT1 and inflammatory responses within breast tumor metastases. Importantly, FLT1 inhibition reduces tumor metastatic efficiency even after initial seeding, suggesting that these pathways represent therapeutic targets in metastatic disease.
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U2 - 10.1084/jem.20141555
DO - 10.1084/jem.20141555
M3 - Article
C2 - 26261265
AN - SCOPUS:84961145493
SN - 0022-1007
VL - 212
SP - 1433
EP - 1448
JO - Journal of Experimental Medicine
JF - Journal of Experimental Medicine
IS - 9
ER -