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; David T. Ting

doi:10.1038/s41467-020-17150-3

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 journal › Article › peer-review

52 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 language	English (US)
Article number	3303
Journal	Nature communications
Volume	11
Issue number	1
DOIs	https://doi.org/10.1038/s41467-020-17150-3
State	Published - Dec 1 2020
Externally published	Yes

ASJC Scopus subject areas

General Chemistry
General
General Biochemistry, Genetics and Molecular Biology
General Physics and Astronomy

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Franses, J. W., Philipp, J., Missios, P., Bhan, I., Liu, A., Yashaswini, C., Tai, E., Zhu, H., Ligorio, M., Nicholson, B., Tassoni, E. M., Desai, N., Kulkarni, A. S., Szabolcs, A., Hong, T. S., Liss, A. S., Fernandez-del Castillo, C., Ryan, D. P., Maheswaran, S., ... Ting, D. T. (2020). Pancreatic circulating tumor cell profiling identifies LIN28B as a metastasis driver and drug target. Nature communications, 11(1), Article 3303. https://doi.org/10.1038/s41467-020-17150-3

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 & Ting, DT 2020, 'Pancreatic circulating tumor cell profiling identifies LIN28B as a metastasis driver and drug target', Nature communications, vol. 11, no. 1, 3303. https://doi.org/10.1038/s41467-020-17150-3

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title = "Pancreatic circulating tumor cell profiling identifies LIN28B as a metastasis driver and drug target",

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.",

author = "Franses, {Joseph W.} and Julia Philipp and Pavlos Missios and Irun Bhan and Ann Liu and Chittampalli Yashaswini and Eric Tai and Huili Zhu and Matteo Ligorio and Benjamin Nicholson and Tassoni, {Elizabeth M.} and Niyati Desai and Kulkarni, {Anupriya S.} and Annamaria Szabolcs and Hong, {Theodore S.} and Liss, {Andrew S.} and {Fernandez-del Castillo}, Carlos and Ryan, {David P.} and Shyamala Maheswaran and Haber, {Daniel A.} and Daley, {George Q.} and Ting, {David T.}",

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AU - Philipp, Julia

AU - Missios, Pavlos

AU - Bhan, Irun

AU - Liu, Ann

AU - Yashaswini, Chittampalli

AU - Tai, Eric

AU - Zhu, Huili

AU - Ligorio, Matteo

AU - Nicholson, Benjamin

AU - Tassoni, Elizabeth M.

AU - Desai, Niyati

AU - Kulkarni, Anupriya S.

AU - Szabolcs, Annamaria

AU - Hong, Theodore S.

AU - Liss, Andrew S.

AU - Fernandez-del Castillo, Carlos

AU - Ryan, David P.

AU - Maheswaran, Shyamala

AU - Haber, Daniel A.

AU - Daley, George Q.

AU - Ting, David T.

PY - 2020/12/1

Y1 - 2020/12/1

N2 - 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.

AB - 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.

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

Abstract

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