Lung Mammary Metastases but Not Primary Tumors Induce Accumulation of Atypical Large Platelets and Their Chemokine Expression

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.