In Vivo Functional Platform Targeting Patient-Derived Xenografts Identifies WDR5-Myc Association as a Critical Determinant of Pancreatic Cancer

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 RivaWantong 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

Research output: Contribution to journalArticle

Abstract

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.

Original languageEnglish
Pages (from-to)133-47
Number of pages15
JournalCell Reports
Volume16
Issue number1
DOIs
Publication statusPublished - Jun 28 2016

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Pancreatic Neoplasms
Heterografts
Tumors
Adenocarcinoma
Methyltransferases
Histones
Allografts
Maintenance
DNA
DNA Replication
Epigenomics
Neoplasms
Survival
Therapeutics

Keywords

  • Journal Article

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In Vivo Functional Platform Targeting Patient-Derived Xenografts Identifies WDR5-Myc Association as a Critical Determinant of Pancreatic Cancer. / Carugo, Alessandro; Genovese, Giannicola; Seth, Sahil; Nezi, Luigi; Rose, Johnathon Lynn; Bossi, Daniela; Cicalese, Angelo; Shah, Parantu Krushnakant; Viale, Andrea; Pettazzoni, Piergiorgio Francesco; Akdemir, Kadir Caner; Bristow, Christopher Aaron; Robinson, Frederick Scott; Tepper, James; Sanchez, Nora; Gupta, Sonal; Estecio, Marcos Roberto; Giuliani, Virginia; Dellino, Gaetano Ivan; Riva, Laura; Yao, Wantong; Di Francesco, Maria Emilia; Green, Tessa; D'Alesio, Carolina; Corti, Denise; Kang, Ya'an; Jones, Philip; Wang, Huamin; Fleming, Jason Bates; Maitra, Anirban; Pelicci, Pier Giuseppe; Chin, Lynda; DePinho, Ronald Anthony; Lanfrancone, Luisa; Heffernan, Timothy Paul; Draetta, Giulio Francesco.

In: Cell Reports, Vol. 16, No. 1, 28.06.2016, p. 133-47.

Research output: Contribution to journalArticle

Carugo, A, Genovese, G, Seth, S, Nezi, L, Rose, JL, Bossi, D, Cicalese, A, Shah, PK, Viale, A, Pettazzoni, PF, Akdemir, KC, Bristow, CA, Robinson, FS, Tepper, J, Sanchez, N, Gupta, S, Estecio, MR, Giuliani, V, Dellino, GI, Riva, L, Yao, W, Di Francesco, ME, Green, T, D'Alesio, C, Corti, D, Kang, Y, Jones, P, Wang, H, Fleming, JB, Maitra, A, Pelicci, PG, Chin, L, DePinho, RA, Lanfrancone, L, Heffernan, TP & Draetta, GF 2016, 'In Vivo Functional Platform Targeting Patient-Derived Xenografts Identifies WDR5-Myc Association as a Critical Determinant of Pancreatic Cancer', Cell Reports, vol. 16, no. 1, pp. 133-47. https://doi.org/10.1016/j.celrep.2016.05.063
Carugo, Alessandro ; Genovese, Giannicola ; Seth, Sahil ; Nezi, Luigi ; Rose, Johnathon Lynn ; Bossi, Daniela ; Cicalese, Angelo ; Shah, Parantu Krushnakant ; Viale, Andrea ; Pettazzoni, Piergiorgio Francesco ; Akdemir, Kadir Caner ; Bristow, Christopher Aaron ; Robinson, Frederick Scott ; Tepper, James ; Sanchez, Nora ; Gupta, Sonal ; Estecio, Marcos Roberto ; Giuliani, Virginia ; Dellino, Gaetano Ivan ; Riva, Laura ; Yao, Wantong ; Di Francesco, Maria Emilia ; Green, Tessa ; D'Alesio, Carolina ; Corti, Denise ; Kang, Ya'an ; Jones, Philip ; Wang, Huamin ; Fleming, Jason Bates ; Maitra, Anirban ; Pelicci, Pier Giuseppe ; Chin, Lynda ; DePinho, Ronald Anthony ; Lanfrancone, Luisa ; Heffernan, Timothy Paul ; Draetta, Giulio Francesco. / In Vivo Functional Platform Targeting Patient-Derived Xenografts Identifies WDR5-Myc Association as a Critical Determinant of Pancreatic Cancer. In: Cell Reports. 2016 ; Vol. 16, No. 1. pp. 133-47.
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T1 - In Vivo Functional Platform Targeting Patient-Derived Xenografts Identifies WDR5-Myc Association as a Critical Determinant of Pancreatic Cancer

AU - Carugo, Alessandro

AU - Genovese, Giannicola

AU - Seth, Sahil

AU - Nezi, Luigi

AU - Rose, Johnathon Lynn

AU - Bossi, Daniela

AU - Cicalese, Angelo

AU - Shah, Parantu Krushnakant

AU - Viale, Andrea

AU - Pettazzoni, Piergiorgio Francesco

AU - Akdemir, Kadir Caner

AU - Bristow, Christopher Aaron

AU - Robinson, Frederick Scott

AU - Tepper, James

AU - Sanchez, Nora

AU - Gupta, Sonal

AU - Estecio, Marcos Roberto

AU - Giuliani, Virginia

AU - Dellino, Gaetano Ivan

AU - Riva, Laura

AU - Yao, Wantong

AU - Di Francesco, Maria Emilia

AU - Green, Tessa

AU - D'Alesio, Carolina

AU - Corti, Denise

AU - Kang, Ya'an

AU - Jones, Philip

AU - Wang, Huamin

AU - Fleming, Jason Bates

AU - Maitra, Anirban

AU - Pelicci, Pier Giuseppe

AU - Chin, Lynda

AU - DePinho, Ronald Anthony

AU - Lanfrancone, Luisa

AU - Heffernan, Timothy Paul

AU - Draetta, Giulio Francesco

N1 - Copyright © 2016 The Authors. Published by Elsevier Inc. All rights reserved.

PY - 2016/6/28

Y1 - 2016/6/28

N2 - 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.

AB - 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.

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JO - Cell Reports

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