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OS2 - 166 A Novel Model of Human Lung-to-Brain Metastasis and its Application to the Identification of Essential Metastatic Regulatory Genes

Published online by Cambridge University Press:  18 October 2016

M Singh*
Affiliation:
Stem Cell and Cancer Research Institute, McMaster University, Hamilton, ON Department of Biochemistry and Biomedical Sciences, McMaster University, Hamilton, ON
C Venugopal
Affiliation:
Stem Cell and Cancer Research Institute, McMaster University, Hamilton, ON Department of Surgery, McMaster University, Hamilton, ON
T Tokar
Affiliation:
Departments of Medical Biophysics and Computer Science, University of Toronto, Toronto, ON
K R Brown
Affiliation:
Donnelly Centre and Department of Molecular Genetics, University of Toronto, ON
N McFarlane
Affiliation:
Stem Cell and Cancer Research Institute, McMaster University, Hamilton, ON Department of Surgery, McMaster University, Hamilton, ON
D Bakhshinyan
Affiliation:
Stem Cell and Cancer Research Institute, McMaster University, Hamilton, ON Department of Biochemistry and Biomedical Sciences, McMaster University, Hamilton, ON
T Vijayakumar
Affiliation:
Stem Cell and Cancer Research Institute, McMaster University, Hamilton, ON Department of Biochemistry and Biomedical Sciences, McMaster University, Hamilton, ON
B Manoranjan
Affiliation:
Stem Cell and Cancer Research Institute, McMaster University, Hamilton, ON Department of Biochemistry and Biomedical Sciences, McMaster University, Hamilton, ON
S Mahendram
Affiliation:
Stem Cell and Cancer Research Institute, McMaster University, Hamilton, ON Department of Surgery, McMaster University, Hamilton, ON
P Vora
Affiliation:
Stem Cell and Cancer Research Institute, McMaster University, Hamilton, ON Department of Surgery, McMaster University, Hamilton, ON
M Qazi
Affiliation:
Stem Cell and Cancer Research Institute, McMaster University, Hamilton, ON Department of Biochemistry and Biomedical Sciences, McMaster University, Hamilton, ON
M Dhillon
Affiliation:
Stem Cell and Cancer Research Institute, McMaster University, Hamilton, ON Department of Surgery, McMaster University, Hamilton, ON
A Tong
Affiliation:
Donnelly Centre and Department of Molecular Genetics, University of Toronto, ON
K Durrer
Affiliation:
Donnelly Centre and Department of Molecular Genetics, University of Toronto, ON
N Murty
Affiliation:
Department of Surgery, McMaster University, Hamilton, ON
R Hallett
Affiliation:
Department of Biochemistry and Biomedical Sciences, McMaster University, Hamilton, ON
J A Hassell
Affiliation:
Department of Biochemistry and Biomedical Sciences, McMaster University, Hamilton, ON
D Kaplan
Affiliation:
Cell Biology Program, The Hospital for Sick Children; Department of Molecular Genetics, University of Toronto, ON
JC Cutz
Affiliation:
Anatomic Pathology, St. Joseph’s Healthcare, Hamilton, ON
I Jurisica
Affiliation:
Princess Margaret Cancer Centre, IBM Life Sciences Discovery Centre, University Health Network, Toronto, ON Departments of Medical Biophysics and Computer Science, University of Toronto, Toronto, ON
J Moffat
Affiliation:
Donnelly Centre and Department of Molecular Genetics, University of Toronto, ON
S K Singh
Affiliation:
Stem Cell and Cancer Research Institute, McMaster University, Hamilton, ON Department of Biochemistry and Biomedical Sciences, McMaster University, Hamilton, ON Department of Surgery, McMaster University, Hamilton, ON
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Abstract

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Brain Metastases (BM) represent a leading cause of cancer mortality. While metastatic lesions contain subclones derived from their primary lesion, their functional characterization has been limited by a paucity of preclinical models accurately recapitulating the stages of metastasis. This work describes the isolation of a unique subset of metastatic stem-like cells from primary human patient samples of BM, termed brain metastasis initiating cells (BMICs). Utilizing these BMICs we have established a novel patient-derived xenograft (PDX) model of BM that recapitulates the entire metastatic cascade, from primary tumor initiation to micro-metastasis and macro-metastasis formation in the brain. We then comprehensively interrogated human BM to identify genetic regulators of BMICs using in vitro and in vivo RNA interference screens, and validated hits using both our novel PDX model as well as primary clinical BM specimens. We identified SPOCK1 and TWIST2 as novel BMIC regulators, where in our model SPOCK1 regulated BMIC self-renewal and tumor initiation, and TWIST2 specifically regulated cell migration from lung to brain. A prospective cohort of primary lung cancer specimens was used to establish that SPOCK1 and TWIST2 were only expressed in patients who ultimately developed BM, thus establishing both clinical and functional utility for these gene products. This work offers the first comprehensive preclinical model of human brain metastasis for further characterization of therapeutic targets, identification of predictive biomarkers, and subsequent prophylactic treatment of patients most likely to develop BM. By blocking this process, metastatic lung cancer would effectively become a localized, more manageable disease.

Type
Oral Presentations
Copyright
Copyright © The Canadian Journal of Neurological Sciences Inc. 2016 
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OS2 - 166 A Novel Model of Human Lung-to-Brain Metastasis and its Application to the Identification of Essential Metastatic Regulatory Genes
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