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

Esmee Koedoot; Michiel Fokkelman; Vasiliki-Maria Rogkoti; Marcel Smid; Iris van de Sandt; Hans de Bont; Chantal Pont; Janna E Klip; Steven Wink; Mieke A Timmermans; Erik A C Wiemer; Peter Stoilov; John A Foekens; Sylvia E Le Dévédec; John W M Martens; Bob van de Water

doi:10.1038/s41467-019-11020-3

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

Nat Commun. 2019 Jul 5;10(1):2983. doi: 10.1038/s41467-019-11020-3.

Authors

Esmee Koedoot¹, Michiel Fokkelman¹, Vasiliki-Maria Rogkoti¹, Marcel Smid², Iris van de Sandt¹, Hans de Bont¹, Chantal Pont¹, Janna E Klip¹, Steven Wink¹, Mieke A Timmermans², Erik A C Wiemer², Peter Stoilov³, John A Foekens², Sylvia E Le Dévédec¹, John W M Martens², Bob van de Water⁴

Affiliations

¹ Division of Drug Discovery and Safety, LACDR, Leiden University, Einsteinweg 55, Leiden, 2333 CC, Netherlands.
² Department of Medical Oncology and Cancer Genomics Netherlands, Erasmus MC Cancer Institute, Erasmus University Medical Center, Rotterdam, 3008 AE, Netherlands.
³ Department of Biochemistry and Cancer Institute, Robert C. Byrd Health Sciences Center, West Virginia University, Morgantown, WV, 26506, USA.
⁴ Division of Drug Discovery and Safety, LACDR, Leiden University, Einsteinweg 55, Leiden, 2333 CC, Netherlands. [email protected].

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.

Publication types

Research Support, Non-U.S. Gov't
Video-Audio Media

MeSH terms

Antigens, Nuclear / genetics
Antigens, Nuclear / metabolism
Cell Line, Tumor
Cell Movement / genetics*
Cohort Studies
Datasets as Topic
Disease-Free Survival
Extracellular Matrix / metabolism
Female
Focal Adhesions / genetics
Gene Expression Regulation, Neoplastic*
Humans
Intravital Microscopy
Nerve Tissue Proteins / genetics
Nerve Tissue Proteins / metabolism
Nuclear Proteins / genetics
Nuclear Proteins / metabolism
Protein Serine-Threonine Kinases / genetics
Protein Serine-Threonine Kinases / metabolism*
RNA Interference
RNA Splicing / genetics
RNA, Small Interfering / metabolism
Ribonucleoprotein, U4-U6 Small Nuclear / genetics
Ribonucleoprotein, U4-U6 Small Nuclear / metabolism*
Signal Transduction / genetics
Survival Analysis
Transcription Factors / genetics
Transcription Factors / metabolism
Triple Negative Breast Neoplasms / genetics
Triple Negative Breast Neoplasms / mortality
Triple Negative Breast Neoplasms / pathology*

Substances

Antigens, Nuclear
BUD31 protein, human
Nerve Tissue Proteins
Nuclear Proteins
RNA, Small Interfering
Ribonucleoprotein, U4-U6 Small Nuclear
Transcription Factors
fetal Alzheimer antigen
PRPF4B protein, human
Protein Serine-Threonine Kinases

Grants and funding

2011-5124/KWF Kankerbestrijding (Dutch Cancer Society)/International