A cell-based high-content screening assay reveals activators and inhibitors of cancer cell invasion

Manuela Quintavalle, Leonardo Elia, Jeffrey H. Price, Susanne Heynen-Genel, Sara Courtneidge

Research output: Contribution to journalArticle

68 Citations (Scopus)

Abstract

Acquisition of invasive cell behavior underlies tumor progression and metastasis. To further define the molecular mechanisms underlying invasive behavior, we developed a high-throughput screening strategy to quantitate invadopodia, which are actin-rich membrane protrusions of cancer cells that contribute to tissue invasion and matrix remodeling. We tested the LOPAC 1280 collection of pharmacologically active agents in a high-content, image-based assay and identified compounds that inhibited invadopodium formation without overt toxicity, as well as compounds that increased invadopodia number. The chemotherapeutic agent paclitaxel increased both the number of invadopodia and the invasive behavior of various human cancer cell lines, effects that have potential clinical implications for its use before surgical removal of a primary tumor (neoadjuvant therapy) or in patients with chemoresistant tumors. Several compounds that inhibited invasion have been characterized as cyclin-dependent kinase (Cdk) inhibitors, and loss-of-function experiments determined that Cdk5 was the relevant target. We further determined that Cdk5 promoted both invadopodium formation and cancer cell invasion by phosphorylating and thus decreasing the abundance of the actin regulatory protein caldesmon.

Original languageEnglish (US)
Article numberra49
JournalScience Signaling
Volume4
Issue number183
DOIs
StatePublished - Jul 26 2011
Externally publishedYes

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Tumors
Assays
Screening
Cells
Actins
Calmodulin-Binding Proteins
Neoplasms
Cyclin-Dependent Kinases
Paclitaxel
Toxicity
Cell Surface Extensions
Throughput
Tissue
Membranes
Neoadjuvant Therapy
Proteins
Experiments
Podosomes
Neoplasm Metastasis
Cell Line

ASJC Scopus subject areas

  • Biochemistry
  • Cell Biology
  • Molecular Biology

Cite this

A cell-based high-content screening assay reveals activators and inhibitors of cancer cell invasion. / Quintavalle, Manuela; Elia, Leonardo; Price, Jeffrey H.; Heynen-Genel, Susanne; Courtneidge, Sara.

In: Science Signaling, Vol. 4, No. 183, ra49, 26.07.2011.

Research output: Contribution to journalArticle

Quintavalle, Manuela ; Elia, Leonardo ; Price, Jeffrey H. ; Heynen-Genel, Susanne ; Courtneidge, Sara. / A cell-based high-content screening assay reveals activators and inhibitors of cancer cell invasion. In: Science Signaling. 2011 ; Vol. 4, No. 183.
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