Tumor-Induced Generation of Splenic Erythroblast-like Ter-Cells Promotes Tumor Progression

Highlights

• Ter-119⁺CD45⁻ erythroblast-like cells were induced in spleen of tumor-bearing mice

• TGF-β and Smad3 activation are important in the generation of splenic Ter-cells

• Splenic Ter-cells produce artemin, and high serum artemin predicts poor prognosis

• Blockade of artemin or its receptor GFRα3 signaling inhibits tumor progression

Summary

Identifying tumor-induced leukocyte subsets and their derived circulating factors has been instrumental in understanding cancer as a systemic disease. Nevertheless, how primary tumor-induced non-leukocyte populations in distal organs contribute to systemic spread remains poorly defined. Here, we report one population of tumor-inducible, erythroblast-like cells (Ter-cells) deriving from megakaryocyte-erythroid progenitor cells with a unique Ter-119⁺CD45⁻CD71⁺ phenotype. Ter-cells are enriched in the enlarged spleen of hosts bearing advanced tumors and facilitate tumor progression by secreting neurotrophic factor artemin into the blood. Transforming growth factor β (TGF-β) and Smad3 activation are important in Ter-cell generation. In vivo blockade of Ter-cell-derived artemin inhibits hepatocellular carcinoma (HCC) growth, and artemin deficiency abolishes Ter-cells’ tumor-promoting ability. We confirm the presence of splenic artemin-positive Ter-cells in human HCC patients and show that significantly elevated serum artemin correlates with poor prognosis. We propose that Ter-cells and the secreted artemin play important roles in cancer progression with prognostic and therapeutic implications.