FLT1 signaling in metastasis-associated macrophages activates an inflammatory signature that promotes breast cancer metastasis.
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.
MRC and University of Edinburgh Centre for Reproductive Health, Queen's Medical Research Institute; and Edinburgh Cancer Research UK Centre, MRC Institute of Genetics and Molecular Medicine; University of Edinburgh, Edinburgh EH16 4TJ, Scotland, UK MRC and University of Edinburgh Centre for Reproductive Health, Queen's Medical Research Institute; and Edinburgh Cancer Research UK Centre, MRC Institute of Genetics and Molecular Medicine; University of Edinburgh, Edinburgh EH16 4TJ, Scotland, UK jeff.pollard@ed.ac.uk binzhi.qian@ed.ac.uk.
Bin-Zhi
BZ
Qian
Department of Developmental and Molecular Biology and Department of Biochemistry, Albert Einstein Cancer Center, Albert Einstein College of Medicine, Bronx, NY 10461.
Hui
H
Zhang
Department of Developmental and Molecular Biology and Department of Biochemistry, Albert Einstein Cancer Center, Albert Einstein College of Medicine, Bronx, NY 10461.
Jiufeng
J
Li
Department of Developmental and Molecular Biology and Department of Biochemistry, Albert Einstein Cancer Center, Albert Einstein College of Medicine, Bronx, NY 10461.
Tianfang
T
He
The Visual Systems Group, Abrahamson Pediatric Eye Institute, Divisions of Pediatric Ophthalmology and Developmental Biology, Cincinnati Children's Hospital Medical Center, Cincinnati, OH 45229 Department of Ophthalmology, University of Cincinnati College of Medicine, Cincinnati, OH 45267.
Eun-Jin
EJ
Yeo
MRC and University of Edinburgh Centre for Reproductive Health, Queen's Medical Research Institute; and Edinburgh Cancer Research UK Centre, MRC Institute of Genetics and Molecular Medicine; University of Edinburgh, Edinburgh EH16 4TJ, Scotland, UK.
Daniel Y H
DY
Soong
MRC and University of Edinburgh Centre for Reproductive Health, Queen's Medical Research Institute; and Edinburgh Cancer Research UK Centre, MRC Institute of Genetics and Molecular Medicine; University of Edinburgh, Edinburgh EH16 4TJ, Scotland, UK.
Neil O
NO
Carragher
MRC and University of Edinburgh Centre for Reproductive Health, Queen's Medical Research Institute; and Edinburgh Cancer Research UK Centre, MRC Institute of Genetics and Molecular Medicine; University of Edinburgh, Edinburgh EH16 4TJ, Scotland, UK.
Alison
A
Munro
Department of Developmental and Molecular Biology and Department of Biochemistry, Albert Einstein Cancer Center, Albert Einstein College of Medicine, Bronx, NY 10461.
Alvin
A
Chang
Department of Developmental and Molecular Biology and Department of Biochemistry, Albert Einstein Cancer Center, Albert Einstein College of Medicine, Bronx, NY 10461.
Anne R
AR
Bresnick
The Visual Systems Group, Abrahamson Pediatric Eye Institute, Divisions of Pediatric Ophthalmology and Developmental Biology, Cincinnati Children's Hospital Medical Center, Cincinnati, OH 45229 Department of Ophthalmology, University of Cincinnati College of Medicine, Cincinnati, OH 45267.
Richard A
RA
Lang
MRC and University of Edinburgh Centre for Reproductive Health, Queen's Medical Research Institute; and Edinburgh Cancer Research UK Centre, MRC Institute of Genetics and Molecular Medicine; University of Edinburgh, Edinburgh EH16 4TJ, Scotland, UK Department of Developmental and Molecular Biology and Department of Biochemistry, Albert Einstein Cancer Center, Albert Einstein College of Medicine, Bronx, NY 10461 jeff.pollard@ed.ac.uk binzhi.qian@ed.ac.uk.
Jeffrey W
JW
Pollard
D000818:Animals; D019898:Autocrine Communication / Q000235:genetics; D001943:Breast Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D005260:Female; D006801:Humans; D016173:Macrophage Colony-Stimulating Factor / Q000235:genetics / Q000378:metabolism; D008264:Macrophages / Q000378:metabolism* / Q000473:pathology; D015674:Mammary Neoplasms, Animal / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D051379:Mice; D008822:Mice, Transgenic; D009362:Neoplasm Metastasis; D009363:Neoplasm Proteins / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction; D040281:Vascular Endothelial Growth Factor Receptor-1 / Q000235:genetics / Q000378:metabolism*
D009363:Neoplasm Proteins; D016173:Macrophage Colony-Stimulating Factor; C501162:FLT1 protein, human; C501163:Flt1 protein, mouse; D040281:Vascular Endothelial Growth Factor Receptor-1