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. Haber, George Q. Daley and David T. Ting ()
Additional contact information
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
George Q. Daley: Harvard Medical School
David T. Ting: Harvard Medical School

Nature Communications, 2020, vol. 11, issue 1, 1-12

Abstract: 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.

Date: 2020
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DOI: 10.1038/s41467-020-17150-3

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