Abstract
The tumor microenvironment (TME) at the metastatic site consists of multiple components with considerable cellular heterogeneity. To test whether endothelial cells (ECs) associated with lung metastases express a distinct gene expression program that promotes metastatic growth, we isolated CD31+/CD45- cells from lung mammary cancer metastases for RNA sequencing and found CD44 upregulation. Unexpectedly, the CD44+ subset did not comprise authentic ECs nor were they bone-marrow-derived CD45- endothelial progenitor cells. Instead, they were a population of large platelets that are distinct from regular small platelets. These CD44+ large platelets were enriched in lung metastases but not primary mammary tumors and upregulated myeloid cell-regulating chemokines indicative of potential regulation of metastasis via indirect mechanisms. Identification of this cellular player in the TME of metastasis suggests a role for the recently identified lung-resident megakaryocytes (MKs) and offers an unexplored route to discover novel mechanisms and an opportunity for therapeutic interventions.