Somatic Tissue Engineering in Mouse Models Reveals an Actionable Role for WNT Pathway Alterations in Prostate Cancer Metastasis
Open Access
- 1 July 2020
- journal article
- research article
- Published by American Association for Cancer Research (AACR) in Cancer Discovery
- Vol. 10 (7), 1038-1057
- https://doi.org/10.1158/2159-8290.cd-19-1242
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. 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. 890Other Versions
Funding Information
- Prostate Cancer (P50 CA092629)
- Memorial Sloan Kettering (P30 CA008748)
- NIH (R01 CA155169, CA193837, CA224079, CA092629, CA160001)
- NIH (CA233944, CA087497)
- NIH (U54 OD020355)
- NIH (R01 CA183929, CA173481)
- STARR Cancer Consortium (I10-0062, I12-0007)
- Agilent
- German Research Foundation
- Shulamit Katzman Endowed Postdoctoral Research Fellowship
- American Cancer Society (PF-16-115-01-TBG)
- NCI (K99 CA241110)
- William C. and Joyce C. O'Neil Charitable Trust
- Memorial Sloan Kettering Single Cell Sequencing Initiative
- Care-for-Rare Foundation
- German Research Foundation
- La Caixa Foundation
- Gerstner Sloan Kettering Graduate School
- NIH (T32CA160001)
- Jane Coffin Childs Memorial Fund
- HHMI
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