FLT1 signaling in metastasis-associated macrophages activates an inflammatory signature that promotes breast cancer metastasis

Bin Zhi Qian, Hui Zhang, Jiufeng Li, Tianfang He, Eun Jin Yeo, Daniel Y H Soong, Neil O. Carragher, Alison Munro, Alvin Chang, Anne R. Bresnick, Richard A. Lang, Jeffrey W. Pollard

Research output: Contribution to journalArticle

72 Citations (Scopus)

Abstract

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.

Original languageEnglish (US)
Pages (from-to)1433-1448
Number of pages16
JournalJournal of Experimental Medicine
Volume212
Issue number9
DOIs
StatePublished - 2015

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Macrophages
Breast Neoplasms
Neoplasm Metastasis
Macrophage Colony-Stimulating Factor
Neoplasms
Autocrine Communication
Lung
Genetic Models
Protein-Tyrosine Kinases
Cause of Death
Inflammation
Growth
Population
Genes

ASJC Scopus subject areas

  • Immunology
  • Immunology and Allergy

Cite this

FLT1 signaling in metastasis-associated macrophages activates an inflammatory signature that promotes breast cancer metastasis. / Qian, Bin Zhi; Zhang, Hui; Li, Jiufeng; He, Tianfang; Yeo, Eun Jin; Soong, Daniel Y H; Carragher, Neil O.; Munro, Alison; Chang, Alvin; Bresnick, Anne R.; Lang, Richard A.; Pollard, Jeffrey W.

In: Journal of Experimental Medicine, Vol. 212, No. 9, 2015, p. 1433-1448.

Research output: Contribution to journalArticle

Qian, BZ, Zhang, H, Li, J, He, T, Yeo, EJ, Soong, DYH, Carragher, NO, Munro, A, Chang, A, Bresnick, AR, Lang, RA & Pollard, JW 2015, 'FLT1 signaling in metastasis-associated macrophages activates an inflammatory signature that promotes breast cancer metastasis', Journal of Experimental Medicine, vol. 212, no. 9, pp. 1433-1448. https://doi.org/10.1084/jem.20141555
Qian, Bin Zhi ; Zhang, Hui ; Li, Jiufeng ; He, Tianfang ; Yeo, Eun Jin ; Soong, Daniel Y H ; Carragher, Neil O. ; Munro, Alison ; Chang, Alvin ; Bresnick, Anne R. ; Lang, Richard A. ; Pollard, Jeffrey W. / FLT1 signaling in metastasis-associated macrophages activates an inflammatory signature that promotes breast cancer metastasis. In: Journal of Experimental Medicine. 2015 ; Vol. 212, No. 9. pp. 1433-1448.
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