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Molecular Cancer Research
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Oncogenes and Tumor Suppressors

Modulation of Mutant KrasG12D-Driven Lung Tumorigenesis In Vivo by Gain or Loss of PCDH7 Function

Xiaorong Zhou, Mahesh S. Padanad, Bret M. Evers, Bethany Smith, Nicole Novaresi, Shruthy Suresh, James A. Richardson, Emily Stein, Jingfei Zhu, Robert E. Hammer and Kathryn A. O'Donnell
Xiaorong Zhou
1Department of Molecular Biology, UT Southwestern Medical Center, Dallas, Texas.
2Department of Immunology, Nantong University School of Medicine, Nantong, China.
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Mahesh S. Padanad
1Department of Molecular Biology, UT Southwestern Medical Center, Dallas, Texas.
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Bret M. Evers
3Department of Pathology, UT Southwestern Medical Center, Dallas, Texas.
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Bethany Smith
1Department of Molecular Biology, UT Southwestern Medical Center, Dallas, Texas.
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Nicole Novaresi
1Department of Molecular Biology, UT Southwestern Medical Center, Dallas, Texas.
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  • ORCID record for Nicole Novaresi
Shruthy Suresh
1Department of Molecular Biology, UT Southwestern Medical Center, Dallas, Texas.
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James A. Richardson
1Department of Molecular Biology, UT Southwestern Medical Center, Dallas, Texas.
3Department of Pathology, UT Southwestern Medical Center, Dallas, Texas.
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Emily Stein
1Department of Molecular Biology, UT Southwestern Medical Center, Dallas, Texas.
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Jingfei Zhu
1Department of Molecular Biology, UT Southwestern Medical Center, Dallas, Texas.
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Robert E. Hammer
4Department of Biochemistry, UT Southwestern Medical Center, Dallas, Texas.
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Kathryn A. O'Donnell
1Department of Molecular Biology, UT Southwestern Medical Center, Dallas, Texas.
5Harold C. Simmons Comprehensive Cancer Center, UT Southwestern Medical Center, Dallas, Texas.
6Hamon Center for Regenerative Science and Medicine, UT Southwestern Medical Center, Dallas, Texas.
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  • For correspondence: Kathryn.ODonnell@UTSouthwestern.edu
DOI: 10.1158/1541-7786.MCR-18-0739 Published February 2019
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Abstract

PROTOCADHERIN 7 (PCDH7), a transmembrane receptor and member of the Cadherin superfamily, is frequently overexpressed in lung adenocarcinoma and is associated with poor clinical outcome. Although PCDH7 was recently shown to promote transformation and facilitate brain metastasis in lung and breast cancers, decreased PCDH7 expression has also been documented in colorectal, gastric, and invasive bladder cancers. These data suggest context-dependent functions for PCDH7 in distinct tumor types. Given that PCDH7 is a potentially targetable molecule on the surface of cancer cells, further investigation of its role in tumorigenesis in vivo is needed to evaluate the therapeutic potential of its inhibition. Here, we report the analysis of novel PCDH7 gain- and loss-of-function mouse models and provide compelling evidence that this cell-surface protein acts as a potent lung cancer driver. Employing a Cre-inducible transgenic allele, we demonstrated that enforced PCDH7 expression significantly accelerates KrasG12D-driven lung tumorigenesis and potentiates MAPK pathway activation. Furthermore, we performed in vivo somatic genome editing with CRISPR/Cas9 in KrasLSL-G12D; Tp53fl/fl (KP) mice to assess the consequences of PCDH7 loss of function. Inactivation of PCDH7 in KP mice significantly reduced lung tumor development, prolonged survival, and diminished phospho-activation of ERK1/2. Together, these findings establish a critical oncogenic function for PCDH7 in vivo and highlight the therapeutic potential of PCDH7 inhibition for lung cancer. Moreover, given recent reports of elevated or reduced PCDH7 in distinct tumor types, the new inducible transgenic model described here provides a robust experimental system for broadly elucidating the effects of PCDH7 overexpression in vivo.

Implications: In this study, we establish a critical oncogenic function for PCDH7 in vivo using novel mouse models and CRISPR/Cas9 genome editing, and we validate the therapeutic potential of PCDH7 inhibition for lung cancer.

This article is featured in Highlights of This Issue, p. 335

Footnotes

  • Note: Supplementary data for this article are available at Molecular Cancer Research Online (http://mcr.aacrjournals.org/).

  • Received July 12, 2018.
  • Revision received September 26, 2018.
  • Accepted October 30, 2018.
  • Published first November 8, 2018.
  • ©2018 American Association for Cancer Research.
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Molecular Cancer Research: 17 (2)
February 2019
Volume 17, Issue 2
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Modulation of Mutant KrasG12D-Driven Lung Tumorigenesis In Vivo by Gain or Loss of PCDH7 Function
Xiaorong Zhou, Mahesh S. Padanad, Bret M. Evers, Bethany Smith, Nicole Novaresi, Shruthy Suresh, James A. Richardson, Emily Stein, Jingfei Zhu, Robert E. Hammer and Kathryn A. O'Donnell
Mol Cancer Res February 1 2019 (17) (2) 594-603; DOI: 10.1158/1541-7786.MCR-18-0739

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Modulation of Mutant KrasG12D-Driven Lung Tumorigenesis In Vivo by Gain or Loss of PCDH7 Function
Xiaorong Zhou, Mahesh S. Padanad, Bret M. Evers, Bethany Smith, Nicole Novaresi, Shruthy Suresh, James A. Richardson, Emily Stein, Jingfei Zhu, Robert E. Hammer and Kathryn A. O'Donnell
Mol Cancer Res February 1 2019 (17) (2) 594-603; DOI: 10.1158/1541-7786.MCR-18-0739
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