Leibold, Josef, Ruscetti, Marcus, Cao, Zhen, Ho, Yu-Jui, Baslan, Timour, Zou, Min, Abida, Wassim, Feucht, Judith, Han, Teng, Barriga, Francisco M, Tsanov, Kaloyan M, Zamechek, Leah, Kulick, Amanda, Amor, Corina, Tian, Sha, Rybczyk, Katarzyna, Salgado, Nelson R, Sánchez-Rivera, Francisco J, Watson, Philip A, de Stanchina, Elisa, Wilkinson, John E, Dow, Lukas E, Abate-Shen, Cory, Sawyers, Charles L, Lowe, Scott W (July 2020) Somatic Tissue Engineering in Mouse Models Reveals an Actionable Role for WNT Pathway Alterations in Prostate Cancer Metastasis. Cancer discovery, 10 (7). pp. 1038-1057. ISSN 2159-8290
Abstract
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 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..
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