Abstract
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.
Highlights
Pancreatic ductal adenocarcinoma (PDAC) lethality is due to metastatic dissemination
We utilized circulating tumor cells (CTCs) purified from patients with never-treated localized PDAC (n = 17; Table 1) and metastatic PDAC (n = 18; Table 2); purified healthy donor (HD, n = 21) volunteer blood was utilized as a control (Fig. 1a; Tables 1–2, Supplementary Table 1)
To determine whether there were PDAC CTC correlated gene sets that can be observed with our technology, we performed gene correlation analysis across all genes that were enriched in blood from either localized PDAC (locPDAC) or metastatic PDAC (metPDAC) patients compared with HDs; we identified three major subgroups of correlated genes within PDAC CTCs (Fig. 2a)
Summary
Pancreatic ductal adenocarcinoma (PDAC) lethality is due to metastatic dissemination. The presence of early CTCs was first demonstrated in geneticallyengineered mouse models of preneoplastic pancreatic intraepithelial neoplasia (PanIN)[12] Following these provocative mouse studies, we[13] and others[14] identified cells released from precancerous human pancreatic intraductal papillary mucinous neoplasm (IPMN) tumors in quantities similar to those released by localized early PDACs. Following these provocative mouse studies, we[13] and others[14] identified cells released from precancerous human pancreatic intraductal papillary mucinous neoplasm (IPMN) tumors in quantities similar to those released by localized early PDACs Consistent with these findings, CTCs have been isolated from patients with early-stage prostate cancers[15], most of whom never proceeded to develop overt metastatic disease.
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