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The role of proteases in Twist induced tumor invasion

  • Author(s): Lwin, Thinzar Helmi Min
  • et al.
Abstract

Metastasis is a complex multi-step process by which cancer cells disseminate from a primary site to distant organs. The transcription factor Twist has been shown to play a key role in metastasis in a mouse mammary tumor metastasis model. It has also been implicated in invasive human cancers and correlated with increased incidence of metastasis and poor disease progression in vivo. One cellular function of Twist that contributes to metastasis is to promote Epithelial-Mesenchymal-Transition, allowing cancer cells to lose cell to cell adhesion and gain motility. However, the role of Twist in other steps of the metastatic cascade has not yet been examined. My project focuses on the role of Twist in promoting tumor invasion and the formation of invasive cellular structures called invadopodia. Fluorescent gelatin degradation assays as well as immunofluorescence assays demonstrate that Twist is necessary and sufficient for local matrix degradation and invadopodia formation. It was unclear the mechanism by which Twist induced invadopodia formation. I hypothesize that Twist may regulate proteases that are associated with invadopodia, playing a key role in invadopodia formation and matrix degradation. My study showed that Twist expression specifically upregulated the expression of three proteases associated with invadopodia: ADAM12, FAPa, and DPPIV. I further investigated the role of ADAM12 studying matrix degradation and invadopodia formation. We found that expression of ADAM12 is necessary for proper matrix degradation and functional invadopodia formation. Together, these results indicate that induction of ADAM12 plays a critical role in Twist-induced matrix degradation and local invasion

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