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

Author

Listed:
  • Joseph W. Franses

    (Harvard Medical School)

  • Julia Philipp

    (Harvard Medical School)

  • Pavlos Missios

    (Harvard Medical School)

  • Irun Bhan

    (Harvard Medical School)

  • Ann Liu

    (Harvard Medical School)

  • Chittampalli Yashaswini

    (Harvard Medical School)

  • Eric Tai

    (Harvard Medical School)

  • Huili Zhu

    (Harvard Medical School)

  • Matteo Ligorio

    (Harvard Medical School)

  • Benjamin Nicholson

    (Harvard Medical School)

  • Elizabeth M. Tassoni

    (Harvard Medical School)

  • Niyati Desai

    (Harvard Medical School)

  • Anupriya S. Kulkarni

    (Harvard Medical School)

  • Annamaria Szabolcs

    (Harvard Medical School)

  • Theodore S. Hong

    (Harvard Medical School)

  • Andrew S. Liss

    (Harvard Medical School)

  • Carlos Fernandez-del Castillo

    (Harvard Medical School)

  • David P. Ryan

    (Harvard Medical School)

  • Shyamala Maheswaran

    (Harvard Medical School)

  • Daniel A. Haber

    (Harvard Medical School
    Howard Hughes Medical Institute)

  • George Q. Daley

    (Harvard Medical School)

  • David T. Ting

    (Harvard Medical School)

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.

Suggested Citation

  • 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 & , 2020. "Pancreatic circulating tumor cell profiling identifies LIN28B as a metastasis driver and drug target," Nature Communications, Nature, vol. 11(1), pages 1-12, December.
    • Handle: RePEc:nat:natcom:v:11:y:2020:i:1:d:10.1038_s41467-020-17150-3
    DOI: 10.1038/s41467-020-17150-3
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