In-depth characterization of a new patient-derived xenograft model for metaplastic breast carcinoma to identify viable biologic targets and patterns of matrix evolution within rare tumor types

Attribution 4.0 International (CC BY 4.0)2022-08-252022-08-252021-08-09Matossian, M. D., Chang, T., Wright, M. K., Burks, H. E., Elliott, S., Sabol, R. A., Wathieu, H., Windsor, G. O., Alzoubi, M. S., King, C. T., Bursavich, J. B., Ham, A. M., Savoie, J. J., Nguyen, K., Baddoo, M., Flemington, E., Sirenko, O., Cromwell, E. F., Hebert, K. L., Lau, F., ... Burow, M. E. (2022). In-depth characterization of a new patient-derived xenograft model for metaplastic breast carcinoma to identify viable biologic targets and patterns of matrix evolution within rare tumor types. Clinical & translational oncology : official publication of the Federation of Spanish Oncology Societies and of the National Cancer Institute of Mexico, 24(1), 127-144. https://doi.org/10.1007/s12094-021-02677-81699-3055https://hdl.handle.net/20.500.12503/31647Metaplastic breast carcinoma (MBC) is a rare breast cancer subtype with rapid growth, high rates of metastasis, recurrence and drug resistance, and diverse molecular and histological heterogeneity. Patient-derived xenografts (PDXs) provide a translational tool and physiologically relevant system to evaluate tumor biology of rare subtypes. Here, we provide an in-depth comprehensive characterization of a new PDX model for MBC, TU-BcX-4IC. TU-BcX-4IC is a clinically aggressive tumor exhibiting rapid growth in vivo, spontaneous metastases, and elevated levels of cell-free DNA and circulating tumor cell DNA. Relative chemosensitivity of primary cells derived from TU-BcX-4IC was performed using the National Cancer Institute (NCI) oncology drug set, crystal violet staining, and cytotoxic live/dead immunofluorescence stains in adherent and organoid culture conditions. We employed novel spheroid/organoid incubation methods (Pu.MA system) to demonstrate that TU-BcX-4IC is resistant to paclitaxel. An innovative physiologically relevant system using human adipose tissue was used to evaluate presence of cancer stem cell-like populations ex vivo. Tissue decellularization, cryogenic-scanning electron microscopy imaging and rheometry revealed consistent matrix architecture and stiffness were consistent despite serial transplantation. Matrix-associated gene pathways were essentially unchanged with serial passages, as determined by qPCR and RNA sequencing, suggesting utility of decellularized PDXs for in vitro screens. We determined type V collagen to be present throughout all serial passage of TU-BcX-4IC tumor, suggesting it is required for tumor maintenance and is a potential viable target for MBC. In this study we introduce an innovative and translational model system to study cell-matrix interactions in rare cancer types using higher passage PDX tissue.http://creativecommons.org/licenses/by/4.0/CollagenExtracellular matrixMetaplastic breast carcinomaPatient-derived xenograftTriple negative breast cancerBone Marrow Cells / immunologyBone Marrow Cells / metabolismCell Culture TechniquesCell DifferentiationCells, CulturedCytokines / geneticsCytokines / metabolismEukaryotic Initiation Factor-2 / metabolismHumansImmunomodulationImmunophenotypingInflammation Mediators / metabolismMesenchymal Stem Cells / immunologyMesenchymal Stem Cells / metabolismRegenerative MedicineSequence Analysis, RNASignal TransductionTranscriptomeBone Marrow Cells / immunologyBone Marrow Cells / metabolismCell Culture TechniquesCell DifferentiationCells, CulturedCytokines / geneticsCytokines / metabolismEukaryotic Initiation Factor-2 / metabolismHumansImmunomodulationImmunophenotypingInflammation Mediators / metabolismMesenchymal Stem Cells / immunologyMesenchymal Stem Cells / metabolismRegenerative MedicineSequence Analysis, RNASignal TransductionTranscriptomeIn-depth characterization of a new patient-derived xenograft model for metaplastic breast carcinoma to identify viable biologic targets and patterns of matrix evolution within rare tumor typesArticle© The Author(s) 2021241