ADAM12 induction by Twist1 promotes tumor invasion and metastasis via regulation of invadopodia and focal adhesions

Mark A. Eckert, Miguel Santiago-Medina, Thinzar M. Lwin, Jihoon Kim, Sara Courtneidge, Jing Yang

Research output: Contribution to journalArticle

11 Scopus citations

Abstract

The Twist1 transcription factor promotes tumor invasion andmetastasis by inducing epithelial-mesenchymal transition (EMT) and invadopodiamediated extracellular matrix (ECM) degradation. The critical transcription targets of Twist1 for mediating these events remain to be uncovered. Here,we report that Twist1 strongly induces expression of a disintegrin and metalloproteinase 12 (ADAM12).We observed that the expression levels of Twist1 mRNA and ADAM12 mRNA are tightly correlated in human breast tumors. Knocking down ADAM12 blocked cell invasion in a 3D mammary organoid culture. Suppression of ADAM12 also inhibited Twist1-induced tumor invasion and metastasis in human breast tumor xenografts, without affecting primary tumor formation. Mechanistically, knockdown of ADAM12 in breast cancer cells significantly reduced invadopodia formation and matrix degradation, and simultaneously increased overall cell adhesion to the ECM. Live-imaging analysis showed that knockdown of ADAM12 significantly inhibited focal adhesion turnover.Mechanistically, both the disintegrin and metalloproteinase domains of ADAM12 are required for its function at invadopodia, whereas the metalloproteinase domain is dispensable for its function at focal adhesions. Taken together, these data suggest that ADAM12 plays a crucial role in tumor invasion and metastasis by regulating both invadopodia and focal adhesions.

Original languageEnglish (US)
Pages (from-to)2036-2048
Number of pages13
JournalJournal of Cell Science
Volume130
Issue number12
DOIs
StatePublished - Jun 15 2017

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Keywords

  • ADAM12
  • Focal adhesion
  • Invadopodia
  • Tumor metastasis
  • Twist1

ASJC Scopus subject areas

  • Cell Biology

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