Uncovering the signaling landscape controlling breast cancer cell migration identifies novel metastasis driver genes

Esmee Koedoot, Michiel Fokkelman, Vasiliki-Maria Rogkoti, Marcel Smid, Iris Sandt, Hans Bont, Chantal Pont, Janna E. Klip, Steven Wink, Mieke A. Timmermans, Erik A. C. Wiemer, Peter Stoilov, John A. Foekens, Sylvia E. Dévédec, John W. M. Martens and Bob Water ()
Additional contact information
Esmee Koedoot: LACDR, Leiden University
Michiel Fokkelman: LACDR, Leiden University
Vasiliki-Maria Rogkoti: LACDR, Leiden University
Marcel Smid: Erasmus University Medical Center
Iris Sandt: LACDR, Leiden University
Hans Bont: LACDR, Leiden University
Chantal Pont: LACDR, Leiden University
Janna E. Klip: LACDR, Leiden University
Steven Wink: LACDR, Leiden University
Mieke A. Timmermans: Erasmus University Medical Center
Erik A. C. Wiemer: Erasmus University Medical Center
Peter Stoilov: West Virginia University
John A. Foekens: Erasmus University Medical Center
Sylvia E. Dévédec: LACDR, Leiden University
John W. M. Martens: Erasmus University Medical Center
Bob Water: LACDR, Leiden University

Nature Communications, 2019, vol. 10, issue 1, 1-16

Abstract: Abstract Ttriple-negative breast cancer (TNBC) is an aggressive and highly metastatic breast cancer subtype. Enhanced TNBC cell motility is a prerequisite of TNBC cell dissemination. Here, we apply an imaging-based RNAi phenotypic cell migration screen using two highly motile TNBC cell lines (Hs578T and MDA-MB-231) to provide a repository of signaling determinants that functionally drive TNBC cell motility. We have screened ~4,200 target genes individually and discovered 133 and 113 migratory modulators of Hs578T and MDA-MB-231, respectively, which are linked to signaling networks predictive for breast cancer progression. The splicing factors PRPF4B and BUD31 and the transcription factor BPTF are essential for cancer cell migration, amplified in human primary breast tumors and associated with metastasis-free survival. Depletion of PRPF4B, BUD31 and BPTF causes primarily down regulation of genes involved in focal adhesion and ECM-interaction pathways. PRPF4B is essential for TNBC metastasis formation in vivo, making PRPF4B a candidate for further drug development.

Date: 2019
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DOI: 10.1038/s41467-019-11020-3

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