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Bioprinted spatially defined breast tumor microenvironment models of intratumoral heterogeneity and drug resistance

ABSTRACT: Cellular extracellular matrix (ECM) and spatial heterogeneity of tumor microenvironments (TME) regulate disease progression and treatment efficacy. Developing in vitro models that recapitulate the TME promises to accelerate studies of tumor biology and identify new targets for therapy. Here, we employed extrusion-based, multi-nozzle three-dimensional (3D) bioprinting to spatially pattern triple-negative MDA-MB-231 breast cancer cells, endothelial cells, and human mammary cancer-associated fibroblasts with biomimetic ECM inks. Bioprinted models captured key features of the spatial architecture of human breast tumors, including varying-sized dense regions of cancer cells and surrounding microvessel-rich stroma. Angiogenesis and ECM stiffening occurred in the stromal area but not the cancer cell rich regions, mimicking pathological changes in patient samples. Transcriptomic analyses revealed upregulation of angiogenesis-related and ECM remodeling-related signatures in the stroma region and identified potential ligand-receptor mediators of these processes. Breast cancer cells in distinct parts of the bioprinted TME showed differing sensitivities to chemotherapy, highlighting environmentally mediated drug resistance. In summary, our 3D bioprinted tumor model will act as a platform to discover integrated functions of the TME in cancer biology and therapy.

ORGANISM(S): Homo sapiens

PROVIDER: GSE269415 | GEO | 2024/06/13

REPOSITORIES: GEO

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Project description:The molecular basis of breast cancer invasion and metastasis is not well understood. Our objective was to analyze transcriptome differences between stromal and epithelial cells in normal breast tissue and invasive breast cancer to define the role stroma plays in invasion. Total RNA was isolated from epithelial and stromal cells that were laser captured from normal breast tissue (n=5) and invasive breast cancer (n=28). Gene expression was measured using Affymetrix U133A 2.0 GeneChips. Differential gene expression was evaluated and compared within a model that accounted for cell type (epithelial [E] versus stromal [S]), diagnosis (cancer [C] versus normal [N]) as well as cell type-diagnosis interactions. Compared to NE, the CE transcriptome was highly enriched with genes in proliferative, motility and ECM ontologies. Differences in CS and NS transcriptomes suggested that the ECM was being remodeled in invasive breast cancer, as genes were over-represented in ECM and proteolysis ontologies. Genes more highly expressed in CS compared to CE were primarily ECM components or were involved in the remodeling of ECM, suggesting that ECM biosynthesis and remodeling were initiated in the tumor stromal compartment. Experiment Overall Design: Breast tissue was collected at surgery from patients undergoing surgical resection for invasive breast cancer (n=28) and reduction mammoplasty (n=5). Tissue was cryopreserved in OCT and serial sections were cut using a cryostat. Sections were stained and epithelial and stromal cells were isolated by laser capture microdissection. Total RNA was isolated and target was prepared using NuGen Ribo-SPIA Ovation Technology. Gene expression was measured using Affymetrix U133A 2.0 GeneChips. Gene expression differences were evaluated using a linear model of the Robust Multichip Average gene expression statistic, a model that accounted for cell type (E and S), patient diagnosis (C and N), as well as cell type-diagnosis interactions. Data were examined to determine false discovery rate and were filtered for fold changes in gene expression and p-value.

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Bioprinted spatially defined breast tumor microenvironment models of intratumoral heterogeneity and drug resistance

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