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Identification of Acquired Notch3 Dependency in Metastatic Head and Neck Cancer

38 Pages Posted: 3 Dec 2018 Sneak Peek Status: Under Review

See all articles by Maria Kondratyev

Maria Kondratyev

University Health Network - Princess Margaret Cancer Centre

Aleksandra Pesic

University Health Network - Princess Margaret Cancer Centre

Azin Sayad

University Health Network - Princess Margaret Cancer Centre

Troy Ketela

University Health Network - Princess Margaret Cancer Centre

Natalie Stickle

Princess Margaret Cancer Center - Bioinformatics and HPC Core

Christine Beswick

University Health Network - Princess Margaret Cancer Centre

Zvi Shalev

University Health Network - Princess Margaret Cancer Centre

Stefano Marastoni

University Health Network - Princess Margaret Cancer Centre

Soroush Samadian

University Health Network - Princess Margaret Cancer Centre

Mikhail Bashkurov

Network Biology Collaborative Centre - SMART High-Content Screening Facility

Pedro Boasquevisque

University Health Network - Princess Margaret Cancer Centre

Alessandro Datti

Network Biology Collaborative Centre - SMART High-Content Screening Facility

Trevor J. Pugh

University Health Network - Princess Margaret Cancer Centre

Carl Virtanen

Princess Margaret Cancer Center - Bioinformatics and HPC Core

Jason Moffat

University of Toronto - The Donnelly Centre

Reidar A. Grénman

University of Turku - Turku University Hospital

Marianne Koritzinsky

University Health Network - Princess Margaret Cancer Centre

Bradly G. Wouters

University Health Network - Princess Margaret Cancer Centre

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Abstract

Survival rates for patients with metastatic HNSCC remain low and with not effective available treatments. We conducted genomic and functional genomic analyses in matched sets of HNSCC cell lines derived from primary tumors and their respective metastatic sites. Components of the Notch3 pathway were identified as differentially expressed and essential in metastatic cells. A distinct gene set is induced upon Notch3/Jag2 interaction in metastatic cells and is associated with EMT. We identified an acquired mutation in the EGF domain of Notch3 in one of the metastatic lines and used CRISPR methodology to demonstrate that this mutation drove altered signaling and dependence in the metastatic variant. Finally, we show that suppression of Notch3 improves survival in mice bearing metastatic orthotropic tumors.

Suggested Citation

Kondratyev, Maria and Pesic, Aleksandra and Sayad, Azin and Ketela, Troy and Stickle, Natalie and Beswick, Christine and Shalev, Zvi and Marastoni, Stefano and Samadian, Soroush and Bashkurov, Mikhail and Boasquevisque, Pedro and Datti, Alessandro and Pugh, Trevor J. and Virtanen, Carl and Moffat, Jason and Grénman, Reidar A. and Koritzinsky, Marianne and Wouters, Bradly G., Identification of Acquired Notch3 Dependency in Metastatic Head and Neck Cancer (November 30, 2018). Available at SSRN: https://ssrn.com/abstract=3293686 or http://dx.doi.org/10.2139/ssrn.3293686
This is a paper under consideration at Cell Press and has not been peer-reviewed.

Maria Kondratyev (Contact Author)

University Health Network - Princess Margaret Cancer Centre ( email )

610 University Avenue
Toronto, ON M5G 2M9
Canada

Aleksandra Pesic

University Health Network - Princess Margaret Cancer Centre

610 University Avenue
Toronto, ON M5G 2M9
Canada

Azin Sayad

University Health Network - Princess Margaret Cancer Centre

610 University Avenue
Toronto, ON M5G 2M9
Canada

Troy Ketela

University Health Network - Princess Margaret Cancer Centre

610 University Avenue
Toronto, ON M5G 2M9
Canada

Natalie Stickle

Princess Margaret Cancer Center - Bioinformatics and HPC Core

610 University Avenue
Toronto, ON M5G 2M9
Canada

Christine Beswick

University Health Network - Princess Margaret Cancer Centre

610 University Avenue
Toronto, ON M5G 2M9
Canada

Zvi Shalev

University Health Network - Princess Margaret Cancer Centre

610 University Avenue
Toronto, ON M5G 2M9
Canada

Stefano Marastoni

University Health Network - Princess Margaret Cancer Centre

610 University Avenue
Toronto, ON M5G 2M9
Canada

Soroush Samadian

University Health Network - Princess Margaret Cancer Centre

610 University Avenue
Toronto, ON M5G 2M9
Canada

Mikhail Bashkurov

Network Biology Collaborative Centre - SMART High-Content Screening Facility

Canada

Pedro Boasquevisque

University Health Network - Princess Margaret Cancer Centre

610 University Avenue
Toronto, ON M5G 2M9
Canada

Alessandro Datti

Network Biology Collaborative Centre - SMART High-Content Screening Facility

Canada

Trevor J. Pugh

University Health Network - Princess Margaret Cancer Centre

610 University Avenue
Toronto, ON M5G 2M9
Canada

Carl Virtanen

Princess Margaret Cancer Center - Bioinformatics and HPC Core

610 University Avenue
Toronto, ON M5G 2M9
Canada

Jason Moffat

University of Toronto - The Donnelly Centre

Toronto, Ontario M5S 3G8
Canada

Reidar A. Grénman

University of Turku - Turku University Hospital

Turku, 20014
Finland

Marianne Koritzinsky

University Health Network - Princess Margaret Cancer Centre

610 University Avenue
Toronto, ON M5G 2M9
Canada

Bradly G. Wouters

University Health Network - Princess Margaret Cancer Centre

610 University Avenue
Toronto, ON M5G 2M9
Canada

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