title: Resolving cancer-stroma interfacial signalling and interventions with micropatterned tumour-stromal assays.
abstract: Tumour-stromal interactions are a determining factor in cancer progression. In vivo, the interaction interface is associated with spatially resolved distributions of cancer and stromal phenotypes. Here, we establish a micropatterned tumour-stromal assay (μTSA) with laser capture microdissection to control the location of co-cultured cells and analyse bulk and interfacial tumour-stromal signalling in driving cancer progression. μTSA reveals a spatial distribution of phenotypes in concordance with human oestrogen receptor-positive (ER+) breast cancer samples, and heterogeneous drug activity relative to the tumour-stroma interface. Specifically, an unknown mechanism of reversine is shown in targeting tumour-stromal interfacial interactions using ER+ MCF-7 breast cancer and bone marrow-derived stromal cells. Reversine suppresses MCF-7 tumour growth and bone metastasis in vivo by reducing tumour stromalization including collagen deposition and recruitment of activated stromal cells. This study advocates μTSA as a platform for studying tumour microenvironmental interactions and cancer field effects with applications in drug discovery and development.
authors.affiliation: Department of Surgery, Center for Engineering in Medicine and Surgical Services, Massachusetts General Hospital, Harvard Medical School and the Shriners Hospitals for Children, Boston, Massachusetts 02114, USA.
authors.forename: Keyue
authors.initials: K
authors.lastname: Shen
authors.affiliation: Department of Surgery, Center for Engineering in Medicine and Surgical Services, Massachusetts General Hospital, Harvard Medical School and the Shriners Hospitals for Children, Boston, Massachusetts 02114, USA.
authors.forename: Samantha
authors.initials: S
authors.lastname: Luk
authors.affiliation: Department of Pathology, Molecular Pathology Unit, Massachusetts General Hospital, Charlestown, Massachusetts 02129, USA.
authors.forename: Daniel F
authors.initials: DF
authors.lastname: Hicks
authors.affiliation: Department of Surgery, Center for Engineering in Medicine and Surgical Services, Massachusetts General Hospital, Harvard Medical School and the Shriners Hospitals for Children, Boston, Massachusetts 02114, USA.
authors.forename: Jessica S
authors.initials: JS
authors.lastname: Elman
authors.affiliation: Department of Surgery, Center for Engineering in Medicine and Surgical Services, Massachusetts General Hospital, Harvard Medical School and the Shriners Hospitals for Children, Boston, Massachusetts 02114, USA.
authors.forename: Stefan
authors.initials: S
authors.lastname: Bohr
authors.affiliation: Center for Systems Biology, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts 02114, USA.
authors.forename: Yoshiko
authors.initials: Y
authors.lastname: Iwamoto
authors.affiliation: Department of Surgery, Center for Engineering in Medicine and Surgical Services, Massachusetts General Hospital, Harvard Medical School and the Shriners Hospitals for Children, Boston, Massachusetts 02114, USA.
authors.forename: Ryan
authors.initials: R
authors.lastname: Murray
authors.affiliation: Department of Mechanical Engineering, Massachusetts Institute of Technology, Cambridge, Massachusetts 02139, USA.
authors.forename: Kristen
authors.initials: K
authors.lastname: Pena
authors.affiliation: Department of Surgery, Center for Engineering in Medicine and Surgical Services, Massachusetts General Hospital, Harvard Medical School and the Shriners Hospitals for Children, Boston, Massachusetts 02114, USA.
authors.forename: Fangjing
authors.initials: F
authors.lastname: Wang
authors.affiliation: Department of Surgery, Center for Engineering in Medicine and Surgical Services, Massachusetts General Hospital, Harvard Medical School and the Shriners Hospitals for Children, Boston, Massachusetts 02114, USA.
authors.forename: Erkin
authors.initials: E
authors.lastname: Seker
authors.affiliation: Center for Systems Biology, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts 02114, USA.
authors.forename: Ralph
authors.initials: R
authors.lastname: Weissleder
authors.affiliation: Department of Surgery, Center for Engineering in Medicine and Surgical Services, Massachusetts General Hospital, Harvard Medical School and the Shriners Hospitals for Children, Boston, Massachusetts 02114, USA.
authors.forename: Martin L
authors.initials: ML
authors.lastname: Yarmush
authors.affiliation: Department of Surgery, Center for Engineering in Medicine and Surgical Services, Massachusetts General Hospital, Harvard Medical School and the Shriners Hospitals for Children, Boston, Massachusetts 02114, USA.
authors.forename: Mehmet
authors.initials: M
authors.lastname: Toner
authors.affiliation: Department of Pathology, Molecular Pathology Unit, Massachusetts General Hospital, Charlestown, Massachusetts 02129, USA.
authors.forename: Dennis
authors.initials: D
authors.lastname: Sgroi
authors.affiliation: 1] Department of Surgery, Center for Engineering in Medicine and Surgical Services, Massachusetts General Hospital, Harvard Medical School and the Shriners Hospitals for Children, Boston, Massachusetts 02114, USA [2] Harvard Stem Cell Institute, Cambridge, Massachusetts 02138, USA.
authors.forename: Biju
authors.initials: B
authors.lastname: Parekkadan
mesh_terms: D000818:Animals; D001854:Bone Marrow Cells / Q000378:metabolism; D001859:Bone Neoplasms / Q000473:pathology; D001943:Breast Neoplasms / Q000473:pathology*; D045744:Cell Line, Tumor; D003094:Collagen / Q000378:metabolism; D018450:Disease Progression; D005260:Female; D005347:Fibroblasts / Q000378:metabolism; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic; D049452:Green Fluorescent Proteins / Q000378:metabolism; D006801:Humans; D019394:Ki-67 Antigen / Q000378:metabolism; D008325:Mammary Neoplasms, Experimental / Q000473:pathology; D051379:Mice; D016688:Mice, Inbred NOD; D016513:Mice, SCID; D008833:Microcirculation; D009025:Morpholines / Q000737:chemistry; D009362:Neoplasm Metastasis; D009368:Neoplasm Transplantation; D010641:Phenotype; D011687:Purines / Q000737:chemistry; D015398:Signal Transduction; D017154:Stromal Cells / Q000378:metabolism*
chemical_list: D019394:Ki-67 Antigen; D009025:Morpholines; D011687:Purines; D049452:Green Fluorescent Proteins; D003094:Collagen; C484369:2-(4-morpholinoanilino)-6-cyclohexylaminopurine