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

Date

2021-08-09

Authors

Matossian, M. D.
Chang, T.
Wright, M. K.
Burks, H. E.
Elliott, S.
Sabol, R. A.
Wathieu, H.
Windsor, G. O.
Alzoubi, Madlin S.
King, C. T.

ORCID

0000-0001-6196-3722 (Bunnell, Bruce A.)

Journal Title

Journal ISSN

Volume Title

Publisher

Springer

Abstract

Metaplastic 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.

Description

Citation

Matossian, 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/s12094-021-02677-8

Rights

© The Author(s) 2021

License

Attribution 4.0 International (CC BY 4.0)