Pancreatic ductal adenocarcinoma (PDAC) lethality is due to metastatic dissemination. Characterization of rare, heterogeneous circulating tumor cells (CTCs) can provide insight into metastasis and guide development of novel therapies. Using the CTC-iChip to purify CTCs from PDAC patients for RNA-seq characterization, we identify three major correlated gene sets, with stemness genes LIN28B/KLF4, WNT5A, and LGALS3 enriched in each correlated gene set; only LIN28B CTC expression was prognostic. CRISPR knockout of LIN28B—an oncofetal RNA-binding protein exerting diverse effects via negative regulation of let-7 miRNAs and other RNA targets—in cell and animal models confers a less aggressive/metastatic phenotype. This correlates with de-repression of let-7 miRNAs and is mimicked by silencing of downstream let-7 target HMGA2 or chemical inhibition of LIN28B/let-7 binding. Molecular characterization of CTCs provides a unique opportunity to correlated gene set metastatic profiles, identify drivers of dissemination, and develop therapies targeting the “seeds” of metastasis.

胰腺导管腺癌 (PDAC) 的致死率是由于转移性传播。罕见的异质循环肿瘤细胞 (CTC) 的表征可以提供对转移的洞察并指导新疗法的开发。使用 CTC-iChip 从 PDAC 患者中纯化 CTC 进行 RNA-seq 表征，我们确定了三个主要的相关基因集，其中干性基因LIN28B/KLF4、WNT5A和LGALS3在每个相关基因集中富集；只有LIN28B CTC 表达具有预后意义。LIN28B的CRISPR敲除——一种癌胎 RNA 结合蛋白，通过对 let-7 miRNA 和其他 RNA 靶点的负调控发挥多种作用——在细胞和动物模型中，具有较低的侵袭性/转移性表型。这与 let-7 miRNA 的去抑制相关，并通过下游 let-7 靶向HMGA2的沉默或 LIN28B/let-7 结合的化学抑制来模拟。CTC 的分子特征为关联基因组转移谱、识别传播驱动因素和开发针对转移“种子”的疗法提供了独特的机会。