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

M. D. Matossian, T. Chang, M. K. Wright, H. E. Burks, S. Elliott, R. A. Sabol, H. Wathieu, G. O. Windsor, M. S. Alzoubi, C. T. King, J. B. Bursavich, A. M. Ham, J. J. Savoie, K. Nguyen, M. Baddoo, E. Flemington, O. Sirenko, E. F. Cromwell, K. L. Hebert, F. LauR. Izadpanah, H. Brown, S. Sinha, J. Zabaleta, A. I. Riker, K. Moroz, L. Miele, A. H. Zea, A. Ochoa, B. A. Bunnell, B. M. Collins-Burow, E. C. Martin, M. E. Burow

Research output: Contribution to journalArticlepeer-review

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.

Original languageEnglish
JournalClinical and Translational Oncology
DOIs
StateAccepted/In press - 2021

Keywords

  • Collagen
  • Extracellular matrix
  • Metaplastic breast carcinoma
  • Patient-derived xenograft
  • Triple negative breast cancer

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