Tumor-educated monocyte-dendritic progenitors promote a metastatic switch

Myeloid skewing of hematopoietic cells is a prominent promoter of metastasis. However, little is known about their education and differentiation pattern from hematopoietic stem and progenitor cells (HSPCs) during tumor progression and metastasis. Here we show that metastatic tumors dictate a unique differentiation pattern of HSPCs towards a specific myeloid progeny. Using single cell RNA-sequencing analysis integrated with proteomic screen of tumor secretome, we demonstrate that highly metastatic tumors dictate a long-lived differentiation of HSPCs towards monocyte-dendritic progenitors (MDPs) while low-metastatic tumors promote their differentiation into granulocyte-monocyte progenitors (GMPs). This effect is driven by IL-6 axis that is highly active in metastatic tumors. Consequently, loss and gain of function of IL-6 in tumor cells resulted in decreased and increased metastasis and corresponding MDP levels, respectively. Consistently, IL-6-educated MDPs but not GMPs obtained from highly metastatic tumors, adoptively transferred into mice bearing low metastatic tumors resulted in increased metastasis due to their further differentiation into immunosuppressive (M2) macrophages. Overall, our study reveals a new role for tumor-derived IL-6 that hijacks HSPC differentiation program towards myeloid cells that contribute to metastasis.