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Gene Editing of α6 Integrin Inhibits Muscle Invasive Networks and Increases Cell-Cell Biophysical Properties in
Cynthia S Rubenstein1, Jaime M C Gard1, Mengdie Wang1
1Cancer Biology Research Program, University of Arizona, Tucson, Arizona.
Cancer Research
|July 25, 2019
Summary
Gene editing a specific α6 integrin region blocked prostate cancer's ability to invade smooth muscle. This approach creates a new cancer cell phenotype, offering a novel strategy to prevent metastasis.
Area of Science:
- Cancer Biology
- Molecular Medicine
- Biophysics
Background:
- Prostate cancer invasiveness correlates with extracapsular extension, requiring smooth muscle invasion.
- Integrins are mechanosensors involved in cell-matrix interactions and invasion.
- The role of α6β1 integrin in smooth muscle invasion by prostate cancer is not fully understood.
Purpose of the Study:
- To investigate if a specific extracellular region of laminin-binding α6β1 integrin is essential for prostate cancer smooth muscle invasion.
- To explore the potential of gene editing this integrin region as a therapeutic strategy for preventing prostate cancer metastasis.
Main Methods:
- Utilized gene editing to create prostate cancer cell lines with wild-type (α6WT), knockout (α6KO), and mutant (α6AA) α6 integrin.
- Assessed 3D in vitro invasion through Matrigel and smooth muscle.
- Evaluated in vivo muscle invasion.
- Employed electric cell-substrate impedance testing (ECIS) to measure cell-cell and cell-ECM interactions.
Main Results:
- Prostate cancer cells expressing α6 integrin (DU145 α6WT) formed invasive networks and invaded smooth muscle in vitro and in vivo.
- α6 integrin knockout (DU145 α6KO) and mutant (DU145 α6AA) cells failed to invade muscle and formed cohesive 3D clusters.
- ECIS revealed altered cell-cell impedance in cohesive clusters and defective cell-ECM coverage in α6AA cells.
Conclusions:
- A specific extracellular region of α6 integrin is critical for prostate cancer's ability to invade smooth muscle.
- Gene editing this α6 integrin region generates a non-invasive cancer phenotype with altered biophysical properties.
- Targeting this integrin region via gene editing presents a promising therapeutic strategy to inhibit prostate cancer metastasis.
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