دورية أكاديمية
Somatic Tissue Engineering in Mouse Models Reveals an Actionable Role for WNT Pathway Alterations in Prostate Cancer Metastasis.
العنوان: | Somatic Tissue Engineering in Mouse Models Reveals an Actionable Role for WNT Pathway Alterations in Prostate Cancer Metastasis. |
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المؤلفون: | Leibold J; Department of Cancer Biology and Genetics, Memorial Sloan Kettering Cancer Center, New York, New York., Ruscetti M; Department of Cancer Biology and Genetics, Memorial Sloan Kettering Cancer Center, New York, New York., Cao Z; Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, New York.; Weill Cornell Graduate School of Medical Sciences, Weill Cornell Medicine, New York, New York., Ho YJ; Department of Cancer Biology and Genetics, Memorial Sloan Kettering Cancer Center, New York, New York., Baslan T; Department of Cancer Biology and Genetics, Memorial Sloan Kettering Cancer Center, New York, New York., Zou M; Departments of Pharmacology, Urology, Medicine, Pathology and Cell Biology, and Systems Biology, Herbert Irving Comprehensive Cancer Center, Columbia University Medical Center, New York, New York., Abida W; Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, New York., Feucht J; Center for Cell Engineering and Immunology Program, Memorial Sloan Kettering Cancer Center, New York, New York., Han T; Weill Cornell Graduate School of Medical Sciences, Weill Cornell Medicine, New York, New York.; Sandra and Edward Meyer Cancer Center, Department of Medicine, Weill Cornell Medicine, New York, New York., Barriga FM; Department of Cancer Biology and Genetics, Memorial Sloan Kettering Cancer Center, New York, New York., Tsanov KM; Department of Cancer Biology and Genetics, Memorial Sloan Kettering Cancer Center, New York, New York., Zamechek L; Department of Cancer Biology and Genetics, Memorial Sloan Kettering Cancer Center, New York, New York., Kulick A; Department of Molecular Pharmacology, Memorial Sloan Kettering Cancer Center, New York, New York., Amor C; Department of Cancer Biology and Genetics, Memorial Sloan Kettering Cancer Center, New York, New York., Tian S; Department of Cancer Biology and Genetics, Memorial Sloan Kettering Cancer Center, New York, New York., Rybczyk K; Department of Cancer Biology and Genetics, Memorial Sloan Kettering Cancer Center, New York, New York., Salgado NR; Department of Cancer Biology and Genetics, Memorial Sloan Kettering Cancer Center, New York, New York., Sánchez-Rivera FJ; Department of Cancer Biology and Genetics, Memorial Sloan Kettering Cancer Center, New York, New York., Watson PA; Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, New York., de Stanchina E; Department of Molecular Pharmacology, Memorial Sloan Kettering Cancer Center, New York, New York., Wilkinson JE; Department of Pathology, University of Michigan, Ann Arbor, Michigan., Dow LE; Sandra and Edward Meyer Cancer Center, Department of Medicine, Weill Cornell Medicine, New York, New York., Abate-Shen C; Departments of Pharmacology, Urology, Medicine, Pathology and Cell Biology, and Systems Biology, Herbert Irving Comprehensive Cancer Center, Columbia University Medical Center, New York, New York., Sawyers CL; Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, New York. lowes@mskcc.org sawyersc@mskcc.org.; Howard Hughes Medical Institute, Chevy Chase, Maryland., Lowe SW; Department of Cancer Biology and Genetics, Memorial Sloan Kettering Cancer Center, New York, New York. lowes@mskcc.org sawyersc@mskcc.org.; Howard Hughes Medical Institute, Chevy Chase, Maryland. |
المصدر: | Cancer discovery [Cancer Discov] 2020 Jul; Vol. 10 (7), pp. 1038-1057. Date of Electronic Publication: 2020 May 06. |
نوع المنشور: | Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't |
اللغة: | English |
بيانات الدورية: | Publisher: American Association for Cancer Research Country of Publication: United States NLM ID: 101561693 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 2159-8290 (Electronic) Linking ISSN: 21598274 NLM ISO Abbreviation: Cancer Discov Subsets: MEDLINE |
أسماء مطبوعة: | Original Publication: Philadelphia, PA : American Association for Cancer Research |
مواضيع طبية MeSH: | Prostatic Neoplasms/*genetics , Tissue Engineering/*methods , Wnt Signaling Pathway/*genetics, Animals ; Disease Models, Animal ; Female ; Humans ; Male ; Mice ; Neoplasm Metastasis |
مستخلص: | 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. 890 . (©2020 American Association for Cancer Research.) |
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معلومات مُعتمدة: | R01 CA193837 United States CA NCI NIH HHS; P50 CA092629 United States CA NCI NIH HHS; R01 CA233944 United States CA NCI NIH HHS; P30 CA008748 United States CA NCI NIH HHS; R01 CA155169 United States CA NCI NIH HHS; P01 CA087497 United States CA NCI NIH HHS; U54 CA224079 United States CA NCI NIH HHS; R01 CA183929 United States CA NCI NIH HHS; T32 CA160001 United States CA NCI NIH HHS; U54 OD020355 United States OD NIH HHS; K99 CA241110 United States CA NCI NIH HHS; R01 CA173481 United States CA NCI NIH HHS; United States HHMI Howard Hughes Medical Institute |
تواريخ الأحداث: | Date Created: 20200508 Date Completed: 20211119 Latest Revision: 20221005 |
رمز التحديث: | 20231215 |
مُعرف محوري في PubMed: | PMC7334089 |
DOI: | 10.1158/2159-8290.CD-19-1242 |
PMID: | 32376773 |
قاعدة البيانات: | MEDLINE |
تدمد: | 2159-8290 |
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DOI: | 10.1158/2159-8290.CD-19-1242 |