@article{f2437af69e024db7adf21220f9abb2b9,
title = "Patient-derived scaffolds uncover breast cancer promoting properties of the microenvironment",
abstract = "Tumor cells interact with the microenvironment that specifically supports and promotes tumor development. Key components in the tumor environment have been linked to various aggressive cancer features and can further influence the presence of subpopulations of cancer cells with specific functions, including cancer stem cells and migratory cells. To model and further understand the influence of specific microenvironments we have developed an experimental platform using cell-free patient-derived scaffolds (PDSs) from primary breast cancers infiltrated with standardized breast cancer cell lines. This PDS culture system induced a series of orchestrated changes in differentiation, epithelial-mesenchymal transition, stemness and proliferation of the cancer cell population, where an increased cancer stem cell pool was confirmed using functional assays. Furthermore, global gene expression profiling showed that PDS cultures were similar to xenograft cultures. Mass spectrometry analyses of cell-free PDSs identified subgroups based on their protein composition that were linked to clinical properties, including tumor grade. Finally, we observed that an induction of epithelial-mesenchymal transition-related genes in cancer cells growing on the PDSs were significantly associated with clinical disease recurrences in breast cancer patients. Patient-derived scaffolds thus mimics in vivo-like growth conditions and uncovers unique information about the malignancy-inducing properties of tumor microenvironment.",
keywords = "Breast cancer, Cancer stem cells, Differentiation, Infiltration, Malignancy, Scaffold",
author = "G{\"o}ran Landberg and Paul Fitzpatrick and Pauline Isakson and Emma Jonasson and Joakim Karlsson and Erik Larsson and Andreas Svanstr{\"o}m and Svanheidur Rafnsdottir and Emma Persson and Anna Gustafsson and Daniel Andersson and Jennifer Rosendahl and Sarunas Petronis and Parmida Ranji and Pernilla Gregersson and Ylva Magnusson and Joakim H{\aa}kansson and Anders St{\aa}hlberg",
note = "Funding Information: We thank the people at Departments of Pathology and Surgery, Sahlgrenska University Hospital for technical assistance handling breast cancer samples and Gothenburg University Proteomics Core Facility for their support. This work was supported by grants from Assar Gabrielssons Research Foundation ; BioCARE National Strategic Research Program at University of Gothenburg; Johan Jansson Foundation for Cancer Research; Knut and Alice Wallenberg Foundation, Wallenberg Center for Molecular and Translational Medicine, University of Gothenburg, Sweden; Region V{\"a}stra G{\"o}taland; Swedish Cancer Foundation (PjF 20 0306 , 2016-438 and 2016-486 ); Swedish Foundation for Strategic Research ; Swedish Research Council ( 2017-01392 and 2016-01530 ); Swedish Childhood Cancer Foundation ( 2017-0043) ; the Swedish state under the agreement between the Swedish government and the county councils, the ALF agreement ( 716321 and 721091 ); Wilhelm and Martina Lundgren Foundation for Scientific Research and VINNOVA ( 2017-03737 ). Funding Information: When repopulating PDSs with different breast cancer cell lines, it was obvious that the highly infiltrating cell line MDA-MB-231 [72] generated a tumor-like appearance with different histological differentiation states in various parts of the PDS. Some tumor cells resembled fibroblasts, whereas other cells resembled endothelial cells that lined former vascular areas. More typical cancer cells with large variations in nuclear sizes and massive atypia were also visible. This apparent variation in morphological appearance of the ER-negative breast cancer cell line supports that the specific environment and heterogeneous PDS composition influenced differentiation. Other 3D-based culture systems have been shown to contribute to the differentiation status of cells grown therein. For example, human adipose tissue-derived extracellular matrix, decellularized and cultured with MCF7 cells, closely resembled xenograft growth and was greatly dissimilar from 2D grown cells in terms of morphology, migration, expression of adhesion molecules and sensitivity to drug treatments [73], whilst collagen-based hydrogels serving as 3D matrix for cultured MCF7s have shown diversified morphologies, significantly increased expression of EMT (SNAI1, SNAI2 and TWIST), and pluripotency (SOX2 and POU5F1) markers [74]. Another relevant patient-derived model system studied the properties of both tumor- and non-tumor-derived scaffolds in colon cancer, focusing on macrophage polarization [75]. In addition, synthetic scaffolds such as those composed of polycaprolactone have been shown to induce increases in stem cell-related genes NOTCH1, POUF1, SOX4, FXD8, and KLF4 [17,18]. Another synthetic scaffold culture system based on poly(lactide-co-glycolide) displayed angiogenic and CSC properties [76]. These studies collectively point towards the need for an improved understanding of the tumor microenvironment and its constituent components and furthermore towards the need for links between scaffold composition and clinical data. Through the use of the PDS model system, the influence of a specific scaffold composition can now be visualized and characterized, opening up novel means of matrix research. Further characterization of architecture, biomechanical properties and protein composition of individual PDSs will be important to define their specific roles in relation to cellular phenotype and clinical parameters.We thank the people at Departments of Pathology and Surgery, Sahlgrenska University Hospital for technical assistance handling breast cancer samples and Gothenburg University Proteomics Core Facility for their support. This work was supported by grants from Assar Gabrielssons Research Foundation; BioCARE National Strategic Research Program at University of Gothenburg; Johan Jansson Foundation for Cancer Research; Knut and Alice Wallenberg Foundation, Wallenberg Center for Molecular and Translational Medicine, University of Gothenburg, Sweden; Region V?stra G?taland; Swedish Cancer Foundation (PjF 20 0306, 2016-438 and 2016-486); Swedish Foundation for Strategic Research; Swedish Research Council (2017-01392 and 2016-01530); Swedish Childhood Cancer Foundation (2017-0043); the Swedish state under the agreement between the Swedish government and the county councils, the ALF agreement (716321 and 721091); Wilhelm and Martina Lundgren Foundation for Scientific Research and VINNOVA (2017-03737). Publisher Copyright: {\textcopyright} 2019 The Authors",
year = "2020",
month = mar,
doi = "10.1016/j.biomaterials.2019.119705",
language = "English",
volume = "235",
journal = "Biomaterials",
issn = "0142-9612",
publisher = "Elsevier",
}
