journal contribution
posted on 2023-04-03, 22:20 authored by 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. Sánchez-Rivera, Philip A. Watson, Elisa de Stanchina, John E. Wilkinson, Lukas E. Dow, Cory Abate-Shen, Charles L. Sawyers, Scott W. Lowe <p>Supplementary Figures and Legends</p>
Funding
Prostate Cancer
Memorial Sloan Kettering
NIH
Starr Cancer Consortium
Agilent
German Research Foundation
Shulamit Katzman Endowed Postdoctoral Research Fellowship
American Cancer Society
NCI
William C. and Joyce C. O'Neil Charitable Trust
Memorial Sloan Kettering Single Cell Sequencing Initiative
Care-for-Rare Foundation
La Caixa foundation
Gerstner Sloan Kettering graduate school
Jane Coffin Childs Memorial Fund
HHMI
History
ARTICLE 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 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.
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
