Tumor-educated uncommitted hematopoietic stem cells promote a metastatic switch

Myeloid skewing of hematopoietic cells is a prominent promoter of metastasis. However, the reservoir of these cells in the bone marrow (BM) compartment, their education, immune memory and their differentiation pattern from uncommitted hematopoietic stem cells (HSCs) have not been explored. Here we show that metastatic tumors dictate a unique differentiation pattern of uncommitted HSCs towards myeloid progeny. Single cell RNA-sequencing analysis integrated with proteomic screen of tumor secretome revealed that HSCs differentiate into monocyte-dendritic progenitors (MDP) in highly metastatic tumors but not in low-metastatic tumors which display HSC differentiation into granulocyte-monocyte progenitors (GMP). This effect is driven by IL-6/IL-6R axis which 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, MDPs but not GMPs obtained from highly metastatic tumors, adoptively transferred into mice bearing tumors resulted in increased metastasis. Our study reveals a unique tumor-BM crosstalk that dictates a specific long-lived education of HSCs towards myeloid differentiation, thereby promoting the enrichment of metastasis-associated immune cells in the tumor microenvironment.