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

Tianying Yuan; Xihong Fu; Rongcheng Hu; Xiaochun Zheng; Dong Jiang; Lanyu Jing; Xiaying Kuang; Zhongwei Guo; Xu Luo; Yixin Liu; Xuenong Zou; Gary D Luker; Shengli Mi; Chun Liu; Wei Sun

doi:10.1016/j.tibtech.2024.06.007

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

Trends Biotechnol. 2024 Nov;42(11):1523-1550. doi: 10.1016/j.tibtech.2024.06.007. Epub 2024 Aug 6.

Authors

Tianying Yuan¹, Xihong Fu², Rongcheng Hu², Xiaochun Zheng³, Dong Jiang², Lanyu Jing⁴, Xiaying Kuang⁴, Zhongwei Guo⁵, Xu Luo³, Yixin Liu³, Xuenong Zou⁶, Gary D Luker⁷, Shengli Mi⁸, Chun Liu⁹, Wei Sun¹⁰

Affiliations

¹ Tsinghua-Berkeley Shenzhen Institute, Tsinghua University, 518055, Shenzhen, China; Tsinghua Shenzhen International Graduate School, Tsinghua University, 518055, Shenzhen, China.
² Institute of Precision Medicine, The First Affiliated Hospital of Sun Yat-sen University, 510080, Guangzhou, China; Guangdong Provincial Key Laboratory of Orthopedics and Traumatology, The First Affiliated Hospital of Sun Yat-sen University, 510080, Guangzhou, China.
³ Tsinghua Shenzhen International Graduate School, Tsinghua University, 518055, Shenzhen, China.
⁴ Department of Breast Surgery, The First Affiliated Hospital of Sun Yat-sen University, 510080, Guangzhou, China.
⁵ School of Mechanics and Safety Engineering, Zhengzhou University, 450001, Zhengzhou, China.
⁶ Guangdong Provincial Key Laboratory of Orthopedics and Traumatology, The First Affiliated Hospital of Sun Yat-sen University, 510080, Guangzhou, China.
⁷ Department of Radiology, University of Michigan, Ann Arbor, MI 48109, USA; Department of Biomedical Engineering, University of Michigan, Ann Arbor, MI 48109, USA. Electronic address: [email protected].
⁸ Tsinghua Shenzhen International Graduate School, Tsinghua University, 518055, Shenzhen, China. Electronic address: [email protected].
⁹ Institute of Precision Medicine, The First Affiliated Hospital of Sun Yat-sen University, 510080, Guangzhou, China; Guangdong Provincial Key Laboratory of Orthopedics and Traumatology, The First Affiliated Hospital of Sun Yat-sen University, 510080, Guangzhou, China. Electronic address: [email protected].
¹⁰ Tsinghua-Berkeley Shenzhen Institute, Tsinghua University, 518055, Shenzhen, China; Department of Mechanical Engineering, Biomanufacturing Center, Tsinghua University, 100084, Beijing, China; Department of Mechanical Engineering, Drexel University, Philadelphia, PA 19104, USA. Electronic address: [email protected].

PMID: 39112274
DOI: 10.1016/j.tibtech.2024.06.007

Abstract

Cellular, extracellular matrix (ECM), and spatial heterogeneity of tumor microenvironments (TMEs) 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 used extrusion-based, multi-nozzle 3D bioprinting to spatially pattern triple-negative MDA-MB-231 breast cancer cells, endothelial cells (ECs), and human mammary cancer-associated fibroblasts (HMCAFs) 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 (CCR) 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 (LR) 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.

Keywords: 3D bioprinting; ECM remodeling; drug resistance; spatial heterogeneity; tumor angiogenesis.

MeSH terms

Bioprinting* / methods
Breast Neoplasms* / drug therapy
Breast Neoplasms* / genetics
Breast Neoplasms* / metabolism
Breast Neoplasms* / pathology
Cell Line, Tumor
Drug Resistance, Neoplasm* / genetics
Extracellular Matrix* / drug effects
Extracellular Matrix* / metabolism
Female
Humans
Neovascularization, Pathologic / genetics
Neovascularization, Pathologic / metabolism
Printing, Three-Dimensional
Tumor Microenvironment* / drug effects
Tumor Microenvironment* / genetics