Dataset Information

Gene Editing of ?6 Integrin Inhibits Muscle Invasive Networks and Increases Cell-Cell Biophysical Properties in Prostate Cancer.

ABSTRACT: Human prostate cancer confined to the gland is indolent (low-risk), but tumors outside the capsule are aggressive (high-risk). Extracapsular extension requires invasion within and through a smooth muscle-structured environment. Because integrins respond to biomechanical cues, we used a gene editing approach to determine if a specific region of laminin-binding ?6?1 integrin was required for smooth muscle invasion both in vitro and in vivo. Human tissue specimens showed prostate cancer invasion through smooth muscle and tumor coexpression of ?6 integrin and E-cadherin in a cell-cell location and ?6 integrin in a cell-extracellular matrix (ECM) distribution. Prostate cancer cells expressing ?6 integrin (DU145 ?6WT) produced a 3D invasive network on laminin-containing Matrigel and invaded into smooth muscle both in vitro and in vivo. In contrast, cells without ?6 integrin (DU145 ?6KO) and cells expressing an integrin mutant (DU145 ?6AA) did not produce invasive networks, could not invade muscle both in vitro and in vivo, and surprisingly formed 3D cohesive clusters. Using electric cell-substrate impedance testing, cohesive clusters had up to a 30-fold increase in normalized resistance at 400 Hz (cell-cell impedance) as compared with the DU145 ?6WT cells. In contrast, measurements at 40,000 Hz (cell-ECM coverage) showed that DU145 ?6AA cells were two-fold decreased in normalized resistance and were defective in restoring resistance after a 1 ?mol/L S1P challenge as compared with the DU145 ?6WT cells. The results suggest that gene editing of a specific ?6 integrin extracellular region, not required for normal tissue function, can generate a new biophysical cancer phenotype unable to invade the muscle, presenting a new therapeutic strategy for metastasis prevention in prostate cancer. SIGNIFICANCE: This study shows an innovative strategy to block prostate cancer metastasis and invasion in the muscle through gene editing of a specific ?6 integrin extracellular region.

SUBMITTER: Rubenstein CS

PROVIDER: S-EPMC6750953 | biostudies-literature | 2019 Sep

REPOSITORIES: biostudies-literature

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Gene Editing of α6 Integrin Inhibits Muscle Invasive Networks and Increases Cell-Cell Biophysical Properties in Prostate Cancer.

Rubenstein Cynthia S CS Gard Jaime M C JMC Wang Mengdie M McGrath Julie E JE Ingabire Nadia N Hinton James P JP Marr Kendra D KD Simpson Skyler J SJ Nagle Raymond B RB Miranti Cindy K CK Warfel Noel A NA Garcia Joe G N JGN Arif-Tiwari Hina H Cress Anne E AE

Cancer research 20190723 18

Human prostate cancer confined to the gland is indolent (low-risk), but tumors outside the capsule are aggressive (high-risk). Extracapsular extension requires invasion within and through a smooth muscle-structured environment. Because integrins respond to biomechanical cues, we used a gene editing approach to determine if a specific region of laminin-binding α6β1 integrin was required for smooth muscle invasion both <i>in vitro</i> and <i>in vivo</i>. Human tissue specimens showed prostate canc ...[more]

PMID: 31337652

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Dataset Information

Gene Editing of ?6 Integrin Inhibits Muscle Invasive Networks and Increases Cell-Cell Biophysical Properties in Prostate Cancer.

Publications

Gene Editing of α6 Integrin Inhibits Muscle Invasive Networks and Increases Cell-Cell Biophysical Properties in Prostate Cancer.

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