Patient-Derived Xenografts as an Innovative Surrogate Tumor Model for the Investigation of Health Disparities in Triple Negative Breast Cancer

Abstract

Despite a decline in overall incidence rates for cancer in the past decade, due in part to impressive advancements in both diagnosis and treatment, breast cancer (BC) remains the leading cause of cancer-related deaths in women. BC alone accounts for *30% of all new cancer diagnoses in women worldwide. Triple-negative BC (TNBC), defined as having no expression of the estrogen or progesterone receptors and no amplification of the HER2 receptor, is a subtype of BC that does not benefit from the use of estrogen receptor-targeting or HER2-targeting therapies. Differences in socioeconomic factors and cell intrinsic and extrinsic characteristics have been demonstrated in Black and White TNBC patient tumors. The emergence of patient-derived xenograft (PDX) models as a surrogate, translational, and functional representation of the patient with TNBC has led to the advances in drug discovery and testing of novel targeted approaches and combination therapies. However, current established TNBC PDX models fail to represent the diverse patient population and, most importantly, the specific ethnic patient populations that have higher rates of incidence and mortality. The primary aim of this review is to emphasize the importance of using clinically relevant translatable tumor models that reflect TNBC human tumor biology and heterogeneity in high-risk patient populations. The focus is to highlight the complexity of BC as it specifically relates to the management of TNBC in Black women. We discuss the importance of utilizing PDX models to study the extracellular matrix (ECM), and the distinct differences in ECM composition and biophysical properties in Black and White women. Finally, we demonstrate the crucial importance of PDX models toward novel drug discovery in this patient population.

Toosendanin induces apoptosis in Oral Squamous Cell Carcinoma cells through inhibition of p-STAT3 and inhibits tumor growth in a OSCC-PDX model

“…These models have an obvious aw, which is their arti cial in uence on tumor cell lines, which are usually passed along from generation to generation in rich culture media. Genetic and epigenetic heterogeneity of primary tumors may not generally be represented by these models 29,30 .On the other hand, the PDX model retains the differentiation, morphological, structural and molecular biological characteristics of the primary tumor, restores the tumor microenvironment in vivo more accurately, retains the heterogeneity of the original tumor tissue, and improves the accuracy of predicting the antitumor effect of drugs 31,32 . According to the immunohistochemical results of mouse tumor mass and patient tumor, our OSCC-PDX model has high pathological homology with patient tumor, and angiogenesis can be seen in mouse tumor, indicating that this model greatly simulates the tumor microenvironment in vivo and retains the heterogeneity of the original tumor tissue.…”

Recent advances in lab-on-a-chip systems for breast cancer metastasis research

“…PDX models, indeed, mostly represent the TNBC subtype and thus require more improvements in establishing the other molecular subtypes of breast cancer. 56,57 The limitations of in vitro and in vivo models have prompted the development of lab-on-a-chip (LOC) technology as a novel in vitro platform. LOC systems offer a more native-like design complexity that can deepen our understanding of breast cancer biology.…”

“…PDX models, indeed, mostly represent the TNBC subtype and thus require more improvements in establishing the other molecular subtypes of breast cancer. 56,57…”

Adipose Tissue in Breast Cancer Microphysiological Models to Capture Human Diversity in Preclinical Models

“…Although there is strong correlative and causative evidence indicating that obesity impacts ASC and adipocyte function and supports the onset and progression of breast cancer, the extent to which it is linked to race is not well understood. Importantly, the breast TME composition and corresponding biomechanical properties (e.g., tissue stiffness, density) differ between races, ethnicities, and age cohorts [ 18 ]. The unique compositional differences in the TME have been demonstrated by profiling resident cell populations, including adipocytes and ASCs, the immune cell landscape, vascular tissue, and the extracellular matrix [ 19 ].…”

“…PDX models for cancer studies typically utilize humanized mouse models to mimic the human immune system. Unlike cell-line-derived xenograft models, PDX models permit the retention of patient tumor heterogeneity, mutations, TME, and endocrine function, making them an ideal model for the evaluation of biomarkers and cell-based therapies, preclinical studies, and personalized medicine approaches [ 18 , 89 ].…”