title: Targeting breast to brain metastatic tumours with death receptor ligand expressing therapeutic stem cells.
abstract: Characterizing clinically relevant brain metastasis models and assessing the therapeutic efficacy in such models are fundamental for the development of novel therapies for metastatic brain cancers. In this study, we have developed an in vivo imageable breast-to-brain metastasis mouse model. Using real time in vivo imaging and subsequent composite fluorescence imaging, we show a widespread distribution of micro- and macro-metastasis in different stages of metastatic progression. We also show extravasation of tumour cells and the close association of tumour cells with blood vessels in the brain thus mimicking the multi-foci metastases observed in the clinics. Next, we explored the ability of engineered adult stem cells to track metastatic deposits in this model and show that engineered stem cells either implanted or injected via circulation efficiently home to metastatic tumour deposits in the brain. Based on the recent findings that metastatic tumour cells adopt unique mechanisms of evading apoptosis to successfully colonize in the brain, we reasoned that TNF receptor superfamily member 10A/10B apoptosis-inducing ligand (TRAIL) based pro-apoptotic therapies that induce death receptor signalling within the metastatic tumour cells might be a favourable therapeutic approach. We engineered stem cells to express a tumour selective, potent and secretable variant of a TRAIL, S-TRAIL, and show that these cells significantly suppressed metastatic tumour growth and prolonged the survival of mice bearing metastatic breast tumours. Furthermore, the incorporation of pro-drug converting enzyme, herpes simplex virus thymidine kinase, into therapeutic S-TRAIL secreting stem cells allowed their eradication post-tumour treatment. These studies are the first of their kind that provide insight into targeting brain metastasis with stem-cell mediated delivery of pro-apoptotic ligands and have important clinical implications.
authors.affiliation: 1 Molecular Neurotherapy and Imaging Laboratory, Massachusetts General Hospital, Harvard Medical School, Boston, MA 02114 USA 2 Department of Radiology, Massachusetts General Hospital, Harvard Medical School, Boston, MA 02114 USA.
authors.forename: Tugba
authors.initials: T
authors.lastname: Bagci-Onder
authors.affiliation: 1 Molecular Neurotherapy and Imaging Laboratory, Massachusetts General Hospital, Harvard Medical School, Boston, MA 02114 USA 2 Department of Radiology, Massachusetts General Hospital, Harvard Medical School, Boston, MA 02114 USA.
authors.forename: Wanlu
authors.initials: W
authors.lastname: Du
authors.affiliation: 1 Molecular Neurotherapy and Imaging Laboratory, Massachusetts General Hospital, Harvard Medical School, Boston, MA 02114 USA.
authors.forename: Jose-Luiz
authors.initials: JL
authors.lastname: Figueiredo
authors.affiliation: 1 Molecular Neurotherapy and Imaging Laboratory, Massachusetts General Hospital, Harvard Medical School, Boston, MA 02114 USA.
authors.forename: Jordi
authors.initials: J
authors.lastname: Martinez-Quintanilla
authors.affiliation: 1 Molecular Neurotherapy and Imaging Laboratory, Massachusetts General Hospital, Harvard Medical School, Boston, MA 02114 USA 2 Department of Radiology, Massachusetts General Hospital, Harvard Medical School, Boston, MA 02114 USA 3 Department of Neurology, Massachusetts General Hospital, Harvard Medical School, Boston, MA 02114 USA 4 Harvard Stem Cell Institute, Harvard University, Cambridge, MA 02138, USA kshah@mgh.harvard.edu.
authors.forename: Khalid
authors.initials: K
authors.lastname: Shah
mesh_terms: D000818:Animals; D001932:Brain Neoplasms / Q000473:pathology / Q000556:secondary* / Q000628:therapy*; D001943:Breast Neoplasms / Q000473:pathology*; D045744:Cell Line, Tumor; D002470:Cell Survival; D005260:Female; D005822:Genetic Vectors / Q000235:genetics; D006801:Humans; D008297:Male; D051379:Mice; D058953:Neural Stem Cells / Q000378:metabolism* / Q000637:transplantation*; D018139:Simplexvirus / Q000201:enzymology / Q000235:genetics; D033581:Stem Cell Transplantation / Q000379:methods*; D053221:TNF-Related Apoptosis-Inducing Ligand / Q000235:genetics / Q000627:therapeutic use*; D013937:Thymidine Kinase / Q000235:genetics / Q000378:metabolism / Q000627:therapeutic use
chemical_list: D053221:TNF-Related Apoptosis-Inducing Ligand; C505654:Tnfsf10 protein, mouse; D013937:Thymidine Kinase
keywords: TRAIL; breast to brain metastasis; death receptor; stem cell