S1PR1-STAT3 Signaling Is Crucial for Myeloid Cell Colonization at Future Metastatic Sites

Abstract

SUMMARY Recent studies underscore the importance of myeloid cells in rendering distant organs hospitable for disseminating tumor cells to colonize. However, what enables myeloid cells to have an apparently superior capacity to colonize distant organs is unclear. Here we show that S1PR1-STAT3 upregulation in tumor cells induces factors that activate S1PR1-STAT3 in various cells in pre-metastatic sites, leading to pre-metastatic niche formation. Targeting either S1PR1 or STAT3 in myeloid cells disrupts existing pre-metastatic niches. S1PR1-STAT3 pathway enables myeloid cells to intravasate, prime the distant organ microenvironment and mediate sustained proliferation and survival of their own and other stromal cells at future metastatic sites. Analyzing tumor-free lymph nodes from cancer patients shows elevated myeloid infiltrates, STAT3 activity and increased survival signal.

From sentinel cells to inflammatory culprits: cancer‐associated fibroblasts in tumour‐related inflammation

“…Resident fibroblasts at the secondary site respond to systemic signals originating from the primary tumour by depositing fibronectin at the pre-metastatic organ, thereby priming it for the homing of myeloid cells that support subsequent metastatic settlement [112]. This up-regulation of fibronectin, enabling myeloid cell recruitment, is STAT3 (signal transducer and activator of transcription 3)-dependent: activation of STAT3 in lung fibroblasts via paracrine signalling from melanoma cells contributes to activation of fibroblasts at the metastatic niche and results in the up-regulation of fibronectin and the recruitment of CD11b + myeloid cells [113]. Recruitment of bone marrow-derived CD11b + myeloid cells, known to be crucial for the formation of hospitable conditions for colonization of tumour cells, is Figure 1.…”

Inflammation and skeletal metastasis

“…137 Persistent STAT3 activation has been linked not only to inflammation-induced tumorigenesis but also to the formation of premetastatic niches conditioning the sites of future distant metastases. [138][139][140][141] An amplification loop identified in tumors links the sphingosine 1-phosphate (S1P) signaling through the S1P receptor 1 (S1PR1) and the activation of STAT3, which in turn feeds back to upregulate S1PR1. 133 This pathway results in the upregulation of S1PR1 in the tumor microenvironment leading to continuous STAT3 activation in cancer cells inducing the expression of factors that trigger the same pathway in myeloid cells.…”

Silence STAT3 in the procancer niche…and activate CD8+ T cells to kill premetastatic myeloid intruders

“…By i.p. injection of supernatants from cultured B16-S1pr1 melanoma cells or MB49-S1pr1 bladder tumor cells overexpressing S1pr1 (called TCM for tumor-conditioned medium) into naive mice, the authors previously observed myeloid cell recruitment to the lung in the absence of tumor injection and increased lung metastasis upon systemic tumor inoculation, all these processes being STAT3-dependent [16]. The factor(s) in TCM responsible for these distant effects has (have) not been defined yet, but may involve a broad spectrum of STAT3-regulated cytokines and growth factors [5] that in turn activate the same STAT3 pathway in nontransformed cells including myeloid "intruder" cells in the premetastatic niche (Fig.…”

“…Additionally, several studies have implicated soluble factors (VEGF, TGF-β, S100 inflammatory chemokines) secreted by the primary tumor in the recruitment of VEGFR1 + bone marrowderived hematopoietic progenitor cells [11] and Mac1 + myeloid cells [12] thereby providing an optimal "soil" for tumor cells to survive and to colonize secondary sites for metastasis, hence preparing a "premetastic niche" (reviewed in [13,14]). In this issue of the European Journal of Immunology, Zhang et al [15] use their previously developed protocol [16,17] as a model to study the premetastatic niche provided by myeloidderived cells. The authors had previously shown in mice that expression of sphingosine-1-phosphate receptor-1 (S1PR1), a G protein-coupled receptor for the lysophospholipid sphingosine-1-phosphate (S1P), is elevated in tumors presenting activated phospho-STAT3 [17].…”

“…In this issue of the European Journal of Immunology, Zhang et al [15] use their previously developed protocol [16,17] as a model to study the premetastatic niche provided by myeloidderived cells. The authors had previously shown in mice that expression of sphingosine-1-phosphate receptor-1 (S1PR1), a G protein-coupled receptor for the lysophospholipid sphingosine-1-phosphate (S1P), is elevated in tumors presenting activated phospho-STAT3 [17].…”