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

• Published in: Cancer cell Vol. 21; no. 5; pp. 642 - 654
• Main Authors: Deng, Jiehui, Liu, Yong, Lee, Heehyoung, Herrmann, Andreas, Zhang, Wang, Zhang, Chunyan, Shen, Shudan, Priceman, Saul J., Kujawski, Maciej, Pal, Sumanta K., Raubitschek, Andrew, Hoon, Dave S.B., Forman, Stephen, Figlin, Robert A., Liu, Jie, Jove, Richard, Yu, Hua
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 15-05-2012
• Subjects: Animals; Cell Line, Tumor; Cell Movement; Cell Proliferation; Cell Survival; CpG Islands; Humans; Lung Neoplasms - metabolism; Lung Neoplasms - secondary; Lymph Nodes - metabolism; Lymph Nodes - pathology; Lymphatic Metastasis; Male; Melanoma - metabolism; Melanoma - secondary; Mice; Mice, Knockout; Myeloid Cells - metabolism; Myeloid Cells - pathology; Neoplasm Invasiveness; Neoplasms - metabolism; Neoplasms - pathology; Prostatic Neoplasms - genetics; Prostatic Neoplasms - metabolism; Prostatic Neoplasms - pathology; Receptors, Lysosphingolipid - deficiency; Receptors, Lysosphingolipid - genetics; Receptors, Lysosphingolipid - metabolism; RNA Interference; Signal Transduction; Skin Neoplasms - metabolism; Skin Neoplasms - pathology; STAT3 Transcription Factor - deficiency; STAT3 Transcription Factor - genetics; STAT3 Transcription Factor - metabolism; Time Factors; Transduction, Genetic; Tumor Microenvironment; Urinary Bladder Neoplasms - metabolism; Urinary Bladder Neoplasms - pathology
• ISSN: 1535-6108; 1878-3686
• DOI: 10.1016/j.ccr.2012.03.039

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 premetastatic sites, leading to premetastatic niche formation. Targeting either S1PR1 or STAT3 in myeloid cells disrupts existing premetastatic 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.
► STAT3 is persistently activated in future metastatic sites ► STAT3 facilitates myeloid cell colonization in future metastatic sites ► Crucial role of STAT3 in orchestrating premetastatic niche formation ► Targeting STAT3 in myeloid cells destroys preformed metastatic niches