PEG10 promoter-driven expression of reporter genes enables molecular imaging of lethal prostate cancer

Mariya Shapovalova, John K. Lee, Yingming Li, Donald J.Vander Griend, Ilsa M. Coleman, Peter S. Nelson, Scott M. Dehm, Aaron M. LeBeau

Research output: Contribution to journalArticlepeer-review

1 Scopus citations

Abstract

The retrotransposon-derived paternally expressed gene 10 (PEG10) protein is ordinarily expressed at high levels in the placenta. Recently, it was discovered that PEG10 isoforms promote the progression of prostate cancer to a highly lethal androgen receptor (AR)-negative phenotype. The presence of PEG10 in other subtypes of prostate cancer has not been explored and a utility for PEG10 overexpression has not been developed. Here, we found that in addition to AR-null disease, PEG10 was also expressed in prostate cancer with constitutively active AR-splice variants. A molecular genetic imaging strategy for noninvasive imaging of AR-splice variant prostate cancer was developed by utilizing the cancer specificity of the PEG10 promoter to drive the expression of reporter genes. Plasmid insertion of a PEG10 promoter sequence optimized for enhanced output upstream of a reporter gene allowed detection of prostate cancer by near-infrared and positron emission tomography imaging after systemic administration of the plasmid in vivo. PEG10 expressing subcutaneous xenograft and intratibial tumor models were imaged by both modalities using this molecular genetic imaging strategy. This study demonstrates a preclinical proof-of-concept that the PEG10 promoter is a powerful and specific tool that can be utilized for noninvasive detection of aggressive prostate cancer subtypes.

Original languageEnglish (US)
Pages (from-to)5668-5680
Number of pages13
JournalCancer Research
Volume79
Issue number21
DOIs
StatePublished - Nov 1 2019

Bibliographical note

Funding Information:
We would like to thank Colleen Forster from the Histology and Research Laboratory at the University of Minnesota for IHC analysis. We also received great technical animal support from Meri DuRand and Angela Blum. We are grateful for Dr. Thomas Pengo for assisting us with creating 3D images. We would also like to acknowledge the University Imaging Centers at the University of Minnesota (Minneapolis, MN) for assisting with imaging experiment coordination. This research was supported by a Prostate Cancer Foundation Young Investigator Award (to A.M. LeBeau), a Masonic Cancer Center Brainstorm Award (to A.M. LeBeau), Prostate Cancer Foundation Challenge Awards (to A.M. LeBeau and S.M. Dehm), the Minnesota Partnership for Biotechnology and Medical Genomics Infrastructure Award (MNP IF 16.05 to A.M. LeBeau), NIH/NCI CA090628 Paul Calabresi K12 Award (to A.M. LeBeau), NIH/NCI R01 CA237272 (to A.M. LeBeau), NIH/NCI R01 CA233562 (to A.M. LeBeau), and NIH/NCI R01 CA174777 (to S.M. Dehm). The Prostate Cancer Biorepository Network is funded by the Department of Defense Prostate Cancer Research Program Awards nos. W81XWH-14-2-0182, W81XWH-14-2-0183, W81XWH- 14-2-0185, W81XWH-14-2-0186, and W81XWH-15-2-0062. This work was also supported by the Office of the Assistant Secretary of Defense for Health Affairs, through the Prostate Cancer Research Program Award W81XWH-17-1- 0275 (to M. Shapovalova).

Funding Information:
We would like to thank Colleen Forster from the Histology and Research Laboratory at the University of Minnesota for IHC analysis. We also received great technical animal support from Meri DuRand and Angela Blum. We are grateful for Dr. Thomas Pengo for assisting us with creating 3D images. We would also like to acknowledge the University Imaging Centers at the University of Minnesota (Minneapolis, MN) for assisting with imaging experiment coordination. This research was supported by a Prostate Cancer Foundation Young Investigator Award (to A.M. LeBeau), a Masonic Cancer Center Brainstorm Award (to A.M. LeBeau), Prostate Cancer Foundation Challenge Awards (to A.M. LeBeau and S.M. Dehm), the Minnesota Partnership for Biotechnology and Medical Genomics Infrastructure Award (MNP IF 16.05 to A.M. LeBeau), NIH/NCI CA090628 Paul Calabresi K12 Award (to A.M. LeBeau), NIH/NCI R01 CA237272 (to A.M. LeBeau), NIH/NCI R01 CA233562 (to A.M. LeBeau), and NIH/NCI R01 CA174777 (to S.M. Dehm). The Prostate Cancer Biorepository Network is funded by the Department of Defense Prostate Cancer Research Program Awards nos. W81XWH-14-2-0182, W81XWH-14-2-0183, W81XWH-14-2-0185, W81XWH-14-2-0186, and W81XWH-15-2-0062. This work was also supported by the Office of the Assistant Secretary of Defense for Health Affairs, through the Prostate Cancer Research Program Award W81XWH-17-1-0275 (to M. Shapovalova).

Publisher Copyright:
© 2019 American Association for Cancer Research.

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