Clawson Gary A, Matters Gail L, Xin Ping, McGovern Christopher, Wafula Eric, dePamphilis Claude, Meckley Morgan, Wong Joyce, Stewart Luke, D'Jamoos Christopher, Altman Naomi, Imamura Kawasawa Yuka, Du Zhen, Honaas Loren, Abraham Thomas
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.
PLoS One. 2017 Sep 28;12(9):e0184451. doi: 10.1371/journal.pone.0184451. eCollection 2017.
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.
在这里,我们描述了从胰腺导管腺癌(PDAC)患者血液中分离和鉴定巨噬细胞 - 肿瘤细胞融合体(MTF)的过程。MTF通常为非整倍体,免疫表型特征表明MTF表达PDAC和干细胞的特征性标志物,以及M2极化的巨噬细胞。单细胞RNA测序分析表明,MTF表达许多与癌症进展相关的转录本、LINE1逆转录转座子,以及几种与转移相关的长链非编码转录本(如MALAT1)的非常高水平表达。当将培养的MTF原位移植到小鼠胰腺中时,它们以明显分化良好的细胞岛形式生长,但它们也以“隐形”方式广泛扩散到多个组织中。在移植后4、8或12周时,发现它们分布在多个器官中(包括肝脏、脾脏、肺),以单个细胞或小细胞团的形式出现,在4至12周期间没有形成明显的肿瘤或任何明显进展。我们认为MTF在PDAC发展过程中持续形成,并且它们在癌症进展早期就发生扩散,在远处部位形成“生态位”,以供转移起始细胞随后定植。