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PLoS One. 2017 Sep 28;12(9):e0184451. doi: 10.1371/journal.pone.0184451. eCollection 2017.

"Stealth dissemination" of macrophage-tumor cell fusions cultured from blood of patients with pancreatic ductal adenocarcinoma.

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Gittlen Cancer Research Laboratories and the Department of Pathology, Hershey Medical Center (HMC), Pennsylvania State University (PSU), Hershey, PA, United States of America.
Department of Biochemistry & Molecular Biology, HMC, PSU, Hershey, PA, United States of America.
Department of Biology, Eberly College, University Park (UP), Pennsylvania State University, University Park, PA, United States of America.
Department of Surgery, HMC, PSU, Hershey, PA, United States of America.
Applications Support, Fluidigm Corporation, South San Francisco, CA, United States of America.
Department of Statistics, Eberly College, UP, PSU, University Park, PA, United States of America.
Department of Pharmacology and Biochemistry & Molecular Biology, Institute for Personalized Medicine, HMC, PSU, Hershey, PA, United States of America.
Department of Neural & Behavioral Sciences and Microscopy Imaging Facility, HMC, PSU, Hershey, PA, United States of America.


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 aneuploidy, and immunophenotypic characterizations showed that the MTFs express markers characteristic of PDAC and stem cells, as well as M2-polarized macrophages. Single cell RNASeq analyses showed that the MTFs express many transcripts implicated in cancer progression, LINE1 retrotransposons, and very high levels of several long non-coding transcripts involved in metastasis (such as MALAT1). When cultured MTFs were transplanted orthotopically into mouse pancreas, they grew as obvious well-differentiated islands of cells, but they also disseminated widely throughout multiple tissues in "stealth" fashion. They were found distributed throughout multiple 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 to 12 week period. We suggest that MTFs form continually during PDAC development, and that they disseminate early in cancer progression, forming "niches" at distant sites for subsequent colonization by metastasis-initiating cells.

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