Somatic tissue engineering in mouse models reveals an actionable role for WNT pathway alterations in prostate cancer metastasis.

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.