251. Pancreatic circulating tumor cell profiling identifies LIN28B as a metastasis driver and drug target.
- Author
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Franses JW, Philipp J, Missios P, Bhan I, Liu A, Yashaswini C, Tai E, Zhu H, Ligorio M, Nicholson B, Tassoni EM, Desai N, Kulkarni AS, Szabolcs A, Hong TS, Liss AS, Fernandez-Del Castillo C, Ryan DP, Maheswaran S, Haber DA, Daley GQ, and Ting DT
- Subjects
- Adult, Aged, Animals, Carcinoma, Pancreatic Ductal drug therapy, Carcinoma, Pancreatic Ductal metabolism, Cell Line, Tumor, Cell Movement genetics, Female, Gene Expression Regulation, Neoplastic, HMGA2 Protein metabolism, Humans, Kaplan-Meier Estimate, Kruppel-Like Factor 4, Male, Mice, Inbred NOD, Mice, Knockout, Mice, SCID, Middle Aged, Neoplasm Metastasis, Pancreatic Neoplasms drug therapy, Pancreatic Neoplasms metabolism, RNA-Binding Proteins metabolism, Carcinoma, Pancreatic Ductal genetics, HMGA2 Protein genetics, MicroRNAs genetics, Neoplastic Cells, Circulating metabolism, Pancreatic Neoplasms genetics, RNA-Binding Proteins genetics
- 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.
- Published
- 2020
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