TY - JOUR
T1 - Pancreatic circulating tumor cell profiling identifies LIN28B as a metastasis driver and drug target
AU - Franses, Joseph W.
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.
N1 - Funding Information:
We thank all laboratory members for helpful discussions. This work was supported by the Howard Hughes Medical Institute (D.A.H.), the National Foundation for Cancer Research (D.A.H.), National Institutes of Health (NIH) Grant R01CA129933 (D.A.H.), 2U01EB012493 (D.A.H.), and R01CA235412 (D.T.T.), the Burroughs Wellcome Fund (D.T.T.), the Warshaw Institute for Pancreatic Cancer Research (D.T.T.), the Verville Family Pancreatic Cancer Research Fund (D.T.T.), the NSF PHY-1549535 (D.T.T.), SU2C and Lustgarten Foundation (T.S.H., D.P.R., D.T.T.), the Susan G. Komen for the Cure Grant KG09042 (to S.M.), and the NCI Federal Share Program and Income (S.M.).
Publisher Copyright:
© 2020, The Author(s).
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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U2 - 10.1038/s41467-020-17150-3
DO - 10.1038/s41467-020-17150-3
M3 - Article
C2 - 32620742
AN - SCOPUS:85087418476
SN - 2041-1723
VL - 11
JO - Nature communications
JF - Nature communications
IS - 1
M1 - 3303
ER -