Somatic Tissue Engineering in Mouse Models Reveals an Actionable Role for WNT Pathway Alterations in Prostate Cancer Metastasis
Somatic Tissue Engineering in Mouse Models Reveals an Actionable Role for WNT Pathway Alterations in Prostate Cancer Metastasis
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DOI：
10.1158/2159-8290.cd-19-1242
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发表时间：
2020-07-01
期刊：
影响因子：
28.2
通讯作者：
Lowe, Scott W.
中科院分区：
文献类型：
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作者：
Leibold, Josef;Ruscetti, Marcus;Lowe, Scott W.
为了研究影响晚期前列腺癌进展和治疗反应的遗传因素，我们开发了一种快速灵活的系统，该系统使用组织电穿孔将与人类疾病相关的遗传改变直接引入小鼠前列腺。这些基于电穿孔的基因工程小鼠模型（EPO-GEMM）概括了传统种系模型的特征，并通过模拟与晚期人类疾病相关的遗传因素，可以产生转移性和去势抗性的肿瘤。具有Trp 53改变的肿瘤亚组获得自发性WNT途径改变，其也与人类转移性前列腺癌相关。使用EPO-GEMM方法和基于正交类器官的模型，我们表明WNT通路激活驱动对药理学WNT通路抑制敏感的转移性疾病。因此，通过利用EPO-GEMMs，我们揭示了WNT信号在驱动前列腺癌转移中的功能作用，并验证了WNT通路作为转移性前列腺癌的治疗靶点。意义：我们对驱动转移性前列腺癌的因素的理解受到晚期疾病模型缺乏的限制。在这里，我们开发了前列腺癌的EPO-GEMM，并使用它们来识别和验证WNT通路作为侵袭性转移性疾病的可行驱动因素。
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.