Dual Targeting of Mesenchymal and Amoeboid Motility Hinders Metastatic Behavior

Area of Science:

• Oncology
• Cell Biology
• Cancer Metastasis Research

Background:

• The scaffolding protein NEDD9 (also known as HEF1) is frequently upregulated in human cancers.
• NEDD9 is recognized as a regulator of mesenchymal migration and cancer cell plasticity.
• The specific role of NEDD9 in regulating diverse migration and invasion modes during breast cancer metastasis remains largely unexplored.

Purpose of the Study:

• To investigate the functional significance of NEDD9 in regulating different modes of cell migration and invasion in the context of triple-negative breast cancer (TNBC) metastasis.
• To elucidate the molecular mechanisms by which NEDD9 influences mesenchymal and amoeboid cell motility.
• To evaluate the therapeutic potential of targeting NEDD9, alone or in combination with other inhibitors, to impede breast cancer spread.

Main Methods:

• Utilized gene depletion techniques (e.g., siRNA) to investigate the necessity of NEDD9 in TNBC cell migration and invasion.
• Analyzed cell morphology changes, including the transition between mesenchymal and amoeboid phenotypes.
• Employed molecular assays to assess the activation of key signaling proteins such as Rac1, RhoA, and the phosphorylation status of CTTN.
• Investigated the roles of VAV2 and AURKA in NEDD9-mediated signaling pathways.
• Evaluated the efficacy of dual-targeting strategies (NEDD9 depletion/AURKA inhibition combined with ROCK inhibition) in preclinical xenograft models of breast cancer metastasis.

Main Results:

• NEDD9 is essential for both mesenchymal and amoeboid individual cell migration/invasion in TNBC.
• NEDD9 deficiency induced an amoeboid morphology but significantly impaired overall cell motility.
• NEDD9 promotes mesenchymal migration through VAV2-dependent activation of Rac1 and enhances actin polymerization via AURKA-dependent CTTN phosphorylation.
• NEDD9 plays a role in regulating downstream RhoA signaling effectors, as NEDD9 depletion increased RhoA activity without promoting functional amoeboid motility.
• Combined inhibition of NEDD9 or AURKA with ROCK inhibition resulted in a significant reduction in cancer cell migration and invasion.

Conclusions:

• NEDD9 is a critical regulator of both mesenchymal and amoeboid migration modes in TNBC.
• A dual-targeting strategy combining NEDD9 modulation with ROCK inhibition is a viable and effective therapeutic approach to suppress breast cancer metastasis.
• Further clinical evaluation of this combined regimen is warranted to improve patient survival by impeding disease spread.