Pancreatic circulating tumor cell profiling identifies LIN28B as a metastasis driver and drug target

• DOI: 10.1038/s41467-020-17150-3
• Publication Date: 2020-07-03T10:02:47Z
• Authors: Joseph W. Franses; Julia Philipp; Pavlos Missios; Irun Bhan; Ann Liu; Chittampalli Yash...; Eric Tai; Huili Zhu; Matteo Ligorio; Benjamin Nicholson; Elizabeth M. Tassoni; Niyati Desai; Anupriya S. Kulkarni; Annamaria Szabolcs; Theodore S. Hong; Andrew S. Liss; Carlos Fernandez-...; David P. Ryan; Shyamala Maheswaran; Daniel A. Haber; George Q. Daley; David T. Ting
• Keywords: Oncomir; Circulating tumor cell; Intravasation

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