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-GEMMs) 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 p53 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 pharmacological 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.

Cancer discovery. 2020 May 06 [Epub ahead of print]

Josef Leibold, Marcus Ruscetti, Zhen Cao, Yu-Jui Ho, Timour Baslan, Min Zou, Wassim Abida, Judith Feucht, Teng Han, Francisco M Barriga, Kaloyan M Tsanov, Leah Zamechek, Amanda Kulick, Corina Amor, Sha Tian, Katarzyna Rybczyk, Nelson R Salgado, Francisco J Sanchez-Rivera, Philip A Watson, Elisa de Stanchina, John E Wilkinson, Lukas E Dow, Cory Abate-Shen, Charles L Sawyers, Scott W Lowe

Cancer Biology and Genetics, Memorial Sloan Kettering Cancer Center., Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center., Columbia University Medical Center., Medicine, Memorial Sloan Kettering Cancer Center., Center for Cell Engineering, Memorial Sloan Kettering Cancer Center., Weill Cornell Graduate School of Medical Sciences, Cornell University., Medicine: Liver and Digestive Diseases, Columbia University., Anti-Tumor Assessment Core, Memorial Sloan Kettering Cancer Center., Human Oncology Pathogenesis Program, Memorial Sloan Kettering Cancer Center., Molecular Pharmacology Program, Memorial Sloan Kettering Cancer Center., Unit for Laboratory Animal Medicine, University of Michigan-Ann Arbor., Medicine, Weill Cornell Medicine., Departments of Urology, Medicine, Systems Biology, and Pathology & Cell Biology, Institute of Cancer Genetics, Herbert Irving Comprehensive Cancer Center, Columbia University Medical Center., Cancer Biology and Genetics, Memorial Sloan Kettering Cancer Center .



Source link