“Stealth Dissemination” of Macrophage-Tumor Cell Fusions Cultured from Blood of Patients with Pancreatic Ductal Adenocarcinoma

Circulating tumor cells (CTCs) appear to be involved in early dissemination of many cancers, although which characteristics are important in metastatic spread are not clear. Here we describe isolation and characterization of macrophage-tumor cell fusions (MTFs) from the blood of pancreatic ductal adenocarcinoma (PDAC) patients. The MTFs were generally aneuploid. Immunophenotypic characterizations showed that the MTFs express markers characteristic of PDAC and pancreatic stem cells, as well as markers of M2-polarized macrophages. Single cell RNASeq analyses showed that the MTFs also express many transcripts implicated in cancer progression, LINE1 retrotransposons, and very high levels of several long non-coding transcripts involved in control of metastasis (such as MALAT-1). When cultured MTFs were transplanted orthotopically into pancreas of mice, they grew as obvious well-differentiated islands of cells in the pancreas, but in addition they disseminated widely throughout multiple tissues in “stealth” fashion. They were found distributed throughout multiple different organs at 4, 8, or 12 weeks after transplantation (including liver, spleen, lung), occurring as single cells or small groups of cells, without formation of obvious tumors or any apparent progression over the 4-12 week period. We suggest that MTFs may play a critical role in metastatic progression of PDAC: They may disseminate widely from primary tumors early in development of PDACs, and prepare pre metastatic “niches” for subsequent development of metastatic foci, although they themselves do not appear to form tumors.