In Vivo Functional Platform Targeting Patient-Derived Xenografts Identifies WDR5-Myc Association as a Critical Determinant of Pancreatic Cancer
Current treatment regimens for pancreatic ductal adenocarcinoma (PDAC) yield poor 5-year survival, emphasizing the critical need to identify druggable targets essential for PDAC maintenance. We developed an unbiased and in vivo target discovery approach to identify molecular vulnerabilities in low-p...
| Main Authors: | , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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Elsevier
2016-06-01
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| Series: | Cell Reports |
| Online Access: | http://www.sciencedirect.com/science/article/pii/S2211124716306611 |
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| author | Alessandro Carugo Giannicola Genovese Sahil Seth Luigi Nezi Johnathon Lynn Rose Daniela Bossi Angelo Cicalese Parantu Krushnakant Shah Andrea Viale Piergiorgio Francesco Pettazzoni Kadir Caner Akdemir Christopher Aaron Bristow Frederick Scott Robinson James Tepper Nora Sanchez Sonal Gupta Marcos Roberto Estecio Virginia Giuliani Gaetano Ivan Dellino Laura Riva Wantong Yao Maria Emilia Di Francesco Tessa Green Carolina D’Alesio Denise Corti Ya’an Kang Philip Jones Huamin Wang Jason Bates Fleming Anirban Maitra Pier Giuseppe Pelicci Lynda Chin Ronald Anthony DePinho Luisa Lanfrancone Timothy Paul Heffernan Giulio Francesco Draetta |
| author_facet | Alessandro Carugo Giannicola Genovese Sahil Seth Luigi Nezi Johnathon Lynn Rose Daniela Bossi Angelo Cicalese Parantu Krushnakant Shah Andrea Viale Piergiorgio Francesco Pettazzoni Kadir Caner Akdemir Christopher Aaron Bristow Frederick Scott Robinson James Tepper Nora Sanchez Sonal Gupta Marcos Roberto Estecio Virginia Giuliani Gaetano Ivan Dellino Laura Riva Wantong Yao Maria Emilia Di Francesco Tessa Green Carolina D’Alesio Denise Corti Ya’an Kang Philip Jones Huamin Wang Jason Bates Fleming Anirban Maitra Pier Giuseppe Pelicci Lynda Chin Ronald Anthony DePinho Luisa Lanfrancone Timothy Paul Heffernan Giulio Francesco Draetta |
| author_sort | Alessandro Carugo |
| collection | DOAJ |
| description | Current treatment regimens for pancreatic ductal adenocarcinoma (PDAC) yield poor 5-year survival, emphasizing the critical need to identify druggable targets essential for PDAC maintenance. We developed an unbiased and in vivo target discovery approach to identify molecular vulnerabilities in low-passage and patient-derived PDAC xenografts or genetically engineered mouse model-derived allografts. Focusing on epigenetic regulators, we identified WDR5, a core member of the COMPASS histone H3 Lys4 (H3K4) MLL (1–4) methyltransferase complex, as a top tumor maintenance hit required across multiple human and mouse tumors. Mechanistically, WDR5 functions to sustain proper execution of DNA replication in PDAC cells, as previously suggested by replication stress studies involving MLL1, and c-Myc, also found to interact with WDR5. We indeed demonstrate that interaction with c-Myc is critical for this function. By showing that ATR inhibition mimicked the effects of WDR5 suppression, these data provide rationale to test ATR and WDR5 inhibitors for activity in this disease. |
| first_indexed | 2024-12-13T00:16:13Z |
| format | Article |
| id | doaj.art-f92a64bf21474917a1f9f089f11ae0b4 |
| institution | Directory Open Access Journal |
| issn | 2211-1247 |
| language | English |
| last_indexed | 2024-12-13T00:16:13Z |
| publishDate | 2016-06-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Cell Reports |
| spelling | doaj.art-f92a64bf21474917a1f9f089f11ae0b42022-12-22T00:05:47ZengElsevierCell Reports2211-12472016-06-0116113314710.1016/j.celrep.2016.05.063In Vivo Functional Platform Targeting Patient-Derived Xenografts Identifies WDR5-Myc Association as a Critical Determinant of Pancreatic CancerAlessandro Carugo0Giannicola Genovese1Sahil Seth2Luigi Nezi3Johnathon Lynn Rose4Daniela Bossi5Angelo Cicalese6Parantu Krushnakant Shah7Andrea Viale8Piergiorgio Francesco Pettazzoni9Kadir Caner Akdemir10Christopher Aaron Bristow11Frederick Scott Robinson12James Tepper13Nora Sanchez14Sonal Gupta15Marcos Roberto Estecio16Virginia Giuliani17Gaetano Ivan Dellino18Laura Riva19Wantong Yao20Maria Emilia Di Francesco21Tessa Green22Carolina D’Alesio23Denise Corti24Ya’an Kang25Philip Jones26Huamin Wang27Jason Bates Fleming28Anirban Maitra29Pier Giuseppe Pelicci30Lynda Chin31Ronald Anthony DePinho32Luisa Lanfrancone33Timothy Paul Heffernan34Giulio Francesco Draetta35Department of Genomic Medicine, UT MD Anderson Cancer Center, Houston, TX 77030, USADepartment of Genomic Medicine, UT MD Anderson Cancer Center, Houston, TX 77030, USAInstitute for Applied Cancer Science, UT MD Anderson Cancer Center, Houston, TX 77030, USADepartment of Genomic Medicine, UT MD Anderson Cancer Center, Houston, TX 77030, USADepartment of Genomic Medicine, UT MD Anderson Cancer Center, Houston, TX 77030, USADepartment of Experimental Oncology, European Institute of Oncology, Milan 20139, ItalyDepartment of Experimental Oncology, European Institute of Oncology, Milan 20139, ItalyInstitute for Applied Cancer Science, UT MD Anderson Cancer Center, Houston, TX 77030, USADepartment of Genomic Medicine, UT MD Anderson Cancer Center, Houston, TX 77030, USADepartment of Genomic Medicine, UT MD Anderson Cancer Center, Houston, TX 77030, USADepartment of Genomic Medicine, UT MD Anderson Cancer Center, Houston, TX 77030, USAInstitute for Applied Cancer Science, UT MD Anderson Cancer Center, Houston, TX 77030, USADepartment of Genomic Medicine, UT MD Anderson Cancer Center, Houston, TX 77030, USADepartment of Genomic Medicine, UT MD Anderson Cancer Center, Houston, TX 77030, USADepartment of Genomic Medicine, UT MD Anderson Cancer Center, Houston, TX 77030, USASheikh Ahmed Bin Zayed Al Nahyan Center for Pancreatic Cancer Research, UT MD Anderson Cancer Center, Houston, TX 77030, USADepartment of Epigenetics and Molecular Carcinogenesis, UT MD Anderson Cancer Center, Houston, TX 77030, USAInstitute for Applied Cancer Science, UT MD Anderson Cancer Center, Houston, TX 77030, USADepartment of Experimental Oncology, European Institute of Oncology, Milan 20139, ItalyCenter for Genomic Science of IIT@SEMM, Istituto Italiano di Tecnologia (IIT), Milan 20139, ItalyDepartment of Genomic Medicine, UT MD Anderson Cancer Center, Houston, TX 77030, USADepartment of Genomic Medicine, UT MD Anderson Cancer Center, Houston, TX 77030, USADepartment of Genomic Medicine, UT MD Anderson Cancer Center, Houston, TX 77030, USADepartment of Experimental Oncology, European Institute of Oncology, Milan 20139, ItalyDepartment of Genomic Medicine, UT MD Anderson Cancer Center, Houston, TX 77030, USADepartment of Surgical Oncology, UT MD Anderson Cancer Center, Houston, TX 77030, USADepartment of Genomic Medicine, UT MD Anderson Cancer Center, Houston, TX 77030, USADepartment of Pathology, UT MD Anderson Cancer Center, Houston, TX 77030, USADepartment of Surgical Oncology, UT MD Anderson Cancer Center, Houston, TX 77030, USASheikh Ahmed Bin Zayed Al Nahyan Center for Pancreatic Cancer Research, UT MD Anderson Cancer Center, Houston, TX 77030, USADepartment of Experimental Oncology, European Institute of Oncology, Milan 20139, ItalyDepartment of Genomic Medicine, UT MD Anderson Cancer Center, Houston, TX 77030, USADepartment of Cancer Biology, UT MD Anderson Cancer Center, Houston, TX 77030, USADepartment of Experimental Oncology, European Institute of Oncology, Milan 20139, ItalyC-4 Therapeutics, Cambridge, MA 02142, USADepartment of Genomic Medicine, UT MD Anderson Cancer Center, Houston, TX 77030, USACurrent treatment regimens for pancreatic ductal adenocarcinoma (PDAC) yield poor 5-year survival, emphasizing the critical need to identify druggable targets essential for PDAC maintenance. We developed an unbiased and in vivo target discovery approach to identify molecular vulnerabilities in low-passage and patient-derived PDAC xenografts or genetically engineered mouse model-derived allografts. Focusing on epigenetic regulators, we identified WDR5, a core member of the COMPASS histone H3 Lys4 (H3K4) MLL (1–4) methyltransferase complex, as a top tumor maintenance hit required across multiple human and mouse tumors. Mechanistically, WDR5 functions to sustain proper execution of DNA replication in PDAC cells, as previously suggested by replication stress studies involving MLL1, and c-Myc, also found to interact with WDR5. We indeed demonstrate that interaction with c-Myc is critical for this function. By showing that ATR inhibition mimicked the effects of WDR5 suppression, these data provide rationale to test ATR and WDR5 inhibitors for activity in this disease.http://www.sciencedirect.com/science/article/pii/S2211124716306611 |
| spellingShingle | Alessandro Carugo Giannicola Genovese Sahil Seth Luigi Nezi Johnathon Lynn Rose Daniela Bossi Angelo Cicalese Parantu Krushnakant Shah Andrea Viale Piergiorgio Francesco Pettazzoni Kadir Caner Akdemir Christopher Aaron Bristow Frederick Scott Robinson James Tepper Nora Sanchez Sonal Gupta Marcos Roberto Estecio Virginia Giuliani Gaetano Ivan Dellino Laura Riva Wantong Yao Maria Emilia Di Francesco Tessa Green Carolina D’Alesio Denise Corti Ya’an Kang Philip Jones Huamin Wang Jason Bates Fleming Anirban Maitra Pier Giuseppe Pelicci Lynda Chin Ronald Anthony DePinho Luisa Lanfrancone Timothy Paul Heffernan Giulio Francesco Draetta In Vivo Functional Platform Targeting Patient-Derived Xenografts Identifies WDR5-Myc Association as a Critical Determinant of Pancreatic Cancer Cell Reports |
| title | In Vivo Functional Platform Targeting Patient-Derived Xenografts Identifies WDR5-Myc Association as a Critical Determinant of Pancreatic Cancer |
| title_full | In Vivo Functional Platform Targeting Patient-Derived Xenografts Identifies WDR5-Myc Association as a Critical Determinant of Pancreatic Cancer |
| title_fullStr | In Vivo Functional Platform Targeting Patient-Derived Xenografts Identifies WDR5-Myc Association as a Critical Determinant of Pancreatic Cancer |
| title_full_unstemmed | In Vivo Functional Platform Targeting Patient-Derived Xenografts Identifies WDR5-Myc Association as a Critical Determinant of Pancreatic Cancer |
| title_short | In Vivo Functional Platform Targeting Patient-Derived Xenografts Identifies WDR5-Myc Association as a Critical Determinant of Pancreatic Cancer |
| title_sort | in vivo functional platform targeting patient derived xenografts identifies wdr5 myc association as a critical determinant of pancreatic cancer |
| url | http://www.sciencedirect.com/science/article/pii/S2211124716306611 |
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