Somatic Tissue Engineering in Mouse Models Reveals an Actionable Role for WNT Pathway Alterations in Prostate Cancer Metastasis
| Autor: | Cory Abate-Shen, Lukas E. Dow, Amanda Kulick, Corina Amor, Nelson R. Salgado, Marcus Ruscetti, Teng Han, Philip A. Watson, Kaloyan M. Tsanov, Zhen Cao, Leah Zamechek, Yu-Jui Ho, Judith Feucht, Charles L. Sawyers, Francisco M. Barriga, Sha Tian, Min Zou, Wassim Abida, John E. Wilkinson, Elisa de Stanchina, Francisco J. Sánchez-Rivera, Scott W. Lowe, Josef Leibold, Katarzyna Rybczyk, Timour Baslan |
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| Rok vydání: | 2019 |
| Předmět: |
Male
Tissue Engineering Somatic cell Electroporation Wnt signaling pathway Prostatic Neoplasms Biology medicine.disease Germline Article Metastasis Prostate cancer Disease Models Animal Mice medicine.anatomical_structure Oncology Prostate Genetically Engineered Mouse medicine Cancer research Animals Humans Female Neoplasm Metastasis Wnt Signaling Pathway |
| Zdroj: | Cancer Discov |
| ISSN: | 2159-8290 |
| Popis: | To study genetic factors influencing the progression and therapeutic responses of advanced prostate cancer, we developed a fast and flexible system that introduces genetic alterations relevant to human disease directly into the prostate glands of mice using tissue electroporation. These electroporation-based genetically engineered mouse models (EPO-GEMM) recapitulate features of traditional germline models and, by modeling genetic factors linked to late-stage human disease, can produce tumors that are metastatic and castration-resistant. A subset of tumors with Trp53 alterations acquired spontaneous WNT pathway alterations, which are also associated with metastatic prostate cancer in humans. Using the EPO-GEMM approach and an orthogonal organoid-based model, we show that WNT pathway activation drives metastatic disease that is sensitive to pharmacologic WNT pathway inhibition. Thus, by leveraging EPO-GEMMs, we reveal a functional role for WNT signaling in driving prostate cancer metastasis and validate the WNT pathway as therapeutic target in metastatic prostate cancer. Significance: Our understanding of the factors driving metastatic prostate cancer is limited by the paucity of models of late-stage disease. Here, we develop EPO-GEMMs of prostate cancer and use them to identify and validate the WNT pathway as an actionable driver of aggressive metastatic disease. This article is highlighted in the In This Issue feature, p. 890 |
| Databáze: | OpenAIRE |
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