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.
Highlights
Breast cancer remains the most common cancer affecting women, with 271,270 new cases in 2019 in the United States, with 30% of all new cancer diagnoses in women due to breast cancer [1]
While most triple-negative breast cancer (TNBC) tumors are responsive to neoadjuvant chemotherapy, patients with unresponsive or poorly responsive tumors have overall worse prognoses and higher rates of relapse compared to other breast cancer subtypes [8,9,10,11]
TU-BcX-4IC was classified as Metaplastic breast carcinoma (MBC) with a TNBC subtype, lesion involvement of all four sampled quadrants of the breast, along with cystic degeneration and necrosis (Fig. 1A)
Summary
Breast cancer remains the most common cancer affecting women, with 271,270 new cases in 2019 in the United States, with 30% of all new cancer diagnoses in women due to breast cancer [1]. Metaplastic breast cancer (MBC) is a relatively rare and heterogeneous subtype of TNBC, comprising less than 1% of all breast carcinomas [13]. It is further characterized by neoplastic epithelial differentiation into squamous or mesenchymal-type tissue, resulting in the diverse presence of multiple cell types within the same tumor [14]. Compared to a histologically different breast cancer type, such as infiltrating ductal carcinoma, MBC patients are older in age, more likely to be Black or Hispanic, less likely to have axillary nodal involvement, and more likely to present with larger tumor size and higher grade [16]. Patients with MBC have a lower overall 5-year survival when compared to invasive ductal or lobular carcinomas [17]
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