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

Joseph W. Franses, Julia Philipp, Pavlos Missios, Irun Bhan, Ann Liu, Chittampalli Yashaswini, 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-del Castillo, David P. Ryan, Shyamala Maheswaran, Daniel A. HaberGeorge Q. Daley, David T. Ting

Research output: Contribution to journalArticlepeer-review

5 Scopus citations

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.

Original languageEnglish (US)
Article number3303
JournalNature communications
Volume11
Issue number1
DOIs
StatePublished - Dec 1 2020
Externally publishedYes

ASJC Scopus subject areas

  • Chemistry(all)
  • Biochemistry, Genetics and Molecular Biology(all)
  • Physics and Astronomy(all)

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