title: An Integrative Platform for Three-dimensional Quantitative Analysis of Spatially Heterogeneous Metastasis Landscapes.
abstract: Metastatic microenvironments are spatially and compositionally heterogeneous. This seemingly stochastic heterogeneity provides researchers great challenges in elucidating factors that determine metastatic outgrowth. Herein, we develop and implement an integrative platform that will enable researchers to obtain novel insights from intricate metastatic landscapes. Our two-segment platform begins with whole tissue clearing, staining, and imaging to globally delineate metastatic landscape heterogeneity with spatial and molecular resolution. The second segment of our platform applies our custom-developed SMART 3D (Spatial filtering-based background removal and Multi-chAnnel forest classifiers-based 3D ReconsTruction), a multi-faceted image analysis pipeline, permitting quantitative interrogation of functional implications of heterogeneous metastatic landscape constituents, from subcellular features to multicellular structures, within our large three-dimensional (3D) image datasets. Coupling whole tissue imaging of brain metastasis animal models with SMART 3D, we demonstrate the capability of our integrative pipeline to reveal and quantify volumetric and spatial aspects of brain metastasis landscapes, including diverse tumor morphology, heterogeneous proliferative indices, metastasis-associated astrogliosis, and vasculature spatial distribution. Collectively, our study demonstrates the utility of our novel integrative platform to reveal and quantify the global spatial and volumetric characteristics of the 3D metastatic landscape with unparalleled accuracy, opening new opportunities for unbiased investigation of novel biological phenomena in situ.
authors.affiliation: Department of Biological Sciences, College of Science, University of Notre Dame, Notre Dame, IN 46556, USA.|Mike and Josie Harper Cancer Research Institute, University of Notre Dame, 1234 N. Notre Dame Avenue, South Bend, IN 46617, USA.
authors.forename: Ian H
authors.initials: IH
authors.lastname: Guldner
authors.affiliation: Department of Computer Science and Engineering, College of Engineering, University of Notre Dame, Notre Dame, IN 46556, USA.
authors.forename: Lin
authors.initials: L
authors.lastname: Yang
authors.affiliation: Department of Biological Sciences, College of Science, University of Notre Dame, Notre Dame, IN 46556, USA.|Mike and Josie Harper Cancer Research Institute, University of Notre Dame, 1234 N. Notre Dame Avenue, South Bend, IN 46617, USA.
authors.forename: Kyle R
authors.initials: KR
authors.lastname: Cowdrick
authors.affiliation: Department of Biological Sciences, College of Science, University of Notre Dame, Notre Dame, IN 46556, USA.|Mike and Josie Harper Cancer Research Institute, University of Notre Dame, 1234 N. Notre Dame Avenue, South Bend, IN 46617, USA.
authors.forename: Qingfei
authors.initials: Q
authors.lastname: Wang
authors.affiliation: Department of Biological Sciences, College of Science, University of Notre Dame, Notre Dame, IN 46556, USA.|Mike and Josie Harper Cancer Research Institute, University of Notre Dame, 1234 N. Notre Dame Avenue, South Bend, IN 46617, USA.
authors.forename: Wendy V
authors.initials: WV
authors.lastname: Alvarez Barrios
authors.affiliation: Department of Biological Sciences, College of Science, University of Notre Dame, Notre Dame, IN 46556, USA.|Mike and Josie Harper Cancer Research Institute, University of Notre Dame, 1234 N. Notre Dame Avenue, South Bend, IN 46617, USA.
authors.forename: Victoria R
authors.initials: VR
authors.lastname: Zellmer
authors.affiliation: Department of Computer Science and Engineering, College of Engineering, University of Notre Dame, Notre Dame, IN 46556, USA.
authors.forename: Yizhe
authors.initials: Y
authors.lastname: Zhang
authors.affiliation: Department of Biological Sciences, College of Science, University of Notre Dame, Notre Dame, IN 46556, USA.|Mike and Josie Harper Cancer Research Institute, University of Notre Dame, 1234 N. Notre Dame Avenue, South Bend, IN 46617, USA.
authors.forename: Misha
authors.initials: M
authors.lastname: Host
authors.affiliation: Mike and Josie Harper Cancer Research Institute, University of Notre Dame, 1234 N. Notre Dame Avenue, South Bend, IN 46617, USA.|Department of Applied and Computational Mathematics and Statistics, College of Science, University of Notre Dame, Notre Dame, IN 46556, USA.
authors.forename: Fang
authors.initials: F
authors.lastname: Liu
authors.affiliation: Mike and Josie Harper Cancer Research Institute, University of Notre Dame, 1234 N. Notre Dame Avenue, South Bend, IN 46617, USA.|Department of Computer Science and Engineering, College of Engineering, University of Notre Dame, Notre Dame, IN 46556, USA.
authors.forename: Danny Z
authors.initials: DZ
authors.lastname: Chen
authors.affiliation: Department of Biological Sciences, College of Science, University of Notre Dame, Notre Dame, IN 46556, USA.|Mike and Josie Harper Cancer Research Institute, University of Notre Dame, 1234 N. Notre Dame Avenue, South Bend, IN 46617, USA.
authors.forename: Siyuan
authors.initials: S
authors.lastname: Zhang
mesh_terms: D000818:Animals; D001699:Biometry / Q000379:methods*; D001932:Brain Neoplasms / Q000000981:diagnostic imaging / Q000473:pathology / Q000556:secondary; D051379:Mice; D009362:Neoplasm Metastasis / Q000000981:diagnostic imaging* / Q000473:pathology*; D061848:Optical Imaging / Q000379:methods*; D010336:Pathology / Q000379:methods*