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

Abstract

The Twist1 transcription factor promotes tumor invasion and metastasis 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.

microRNAs Orchestrate Pathophysiology of Breast Cancer Brain Metastasis: Advances in Therapy

“…EMT transcription factors (TFs), such as TWIST1, SNAIL1, and SLUG, are contributory to BC metastatic potential and associated with poor prognosis [81]. ADAM12, a long splice variant with a transmembrane domain and member of the disintegrin and metalloproteinase family [82], can be induced by Twist1, thereby promoting tumor invasion via regulation of invadopodia formation and focal adhesions [83]. MiR-34a suppresses BC metastasis by downregulating EMT-TFs (SLUG, TWIST1, and ZEB1/2) and NOTCH1 signaling [81].…”

Tks adaptor proteins at a glance

“…Interference with this interaction reduces neuronal death. Furthermore, recent reports describe the importance of ADAM12 in the formation of invadopodia, as well as subsequent to their formation (Diaz et al, 2013;Eckert et al, 2017). Thus, this interaction might be explored therapeutically to treat Alzheimer's disease and perhaps also invasive cancer.…”

A proximity-labeling proteomic approach to investigate invadopodia molecular landscape in breast cancer cells

“…In contrast, the zonula occludens protein ZO-1/TJP1 was proposed to regulate degradative activity of invadopodia-like structures through its interaction with ADAM12 and MMP14 35,36 . The ADAM15 metalloproteinase, which was actually suggested to be a Tks5 interactor 22,37 , since its intracellular domain can associate with Tks5, might also function in degradation of the ECM, but, in contrast to ADAM12 38,39 , its function in invadosomes remains to be demonstrated. Finally, the RNA binding protein IGF2BP2/IMP2 was shown to be involved in invadopodia formation through the control of the stability or localization of mRNAs of factors implicated in cell adhesion, mobility, invasion and ECM 40,41 .…”