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Johns Hopkins University

Biomaterials, 2023 Apr 21;298:122128 | https://doi.org/10.1016/j.biomaterials.2023.122128 Tumor stromal topography promotes chemoresistance in migrating breast cancer cell clusters

Chia-Yi Su ^a, Alex Wu ^a, Zhipeng Dong ^b, Chris P. Miller^c, Allister Suarez^a, Andrew J. Ewald ^a,d,e, Eun Hyun Ahn ^a, Deok-Ho Kim^a,b,f

^aDepartment of Biomedical Engineering, Johns Hopkins University, Baltimore, MD, United States
^bDepartment of Mechanical Engineering, Johns Hopkins University, Baltimore, MD, United States
^cClinical Research Division, Fred Hutchinson Cancer Center, Seattle, WA, United States
^dDepartment of Oncology, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, MD, United States
^eDepartment of Cell Biology and Center for Cell Dynamics, Johns Hopkins University School of Medicine, Baltimore, MD, United States
^fDepartment of Medicine, Johns Hopkins University School of Medicine, Baltimore, MD, United States

Corresponding authors: Eun Hyun Ahn, Deok-Ho Kim

Abstract

Multicellular clustering provides cancer cells with survival advantages and facilitates metastasis. At the tumor migration front, cancer cell clusters are surrounded by an aligned stromal topography. It remains unknown whether aligned stromal topography regulates the resistance of migrating cancer cell clusters to therapeutics. Using a hybrid nanopatterned model to characterize breast cancer cell clusters at the migration front with aligned stromal topography, we demonstrate that topography-induced migrating cancer cell clusters exhibit upregulated cytochrome P450 family 1 (CYP1) drug metabolism and downregulated glycolysis gene signatures, which correlates with unfavorable prognosis. Screening on approved oncology drugs shows that cancer cell clusters on aligned stromal topography are more resistant to diverse chemotherapeutics. Full-dose drug testings further indicate that topography induces drug resistance of hormone receptor-positive breast cancer cell clusters to doxorubicin and tamoxifen and triple-negative breast cancer cell clusters to doxorubicin by activating the aryl hydrocarbon receptor (AhR)/CYP1 pathways. Inhibiting the AhR/CYP1 pathway restores reactive oxygen species-mediated drug sensitivity to migrating cancer cell clusters, suggesting a plausible therapeutic direction for preventing metastatic recurrence.

논문정보

형식Research article
게재일2023년 04월 (BRIC 등록일 2023-06-02)
연구진국외 연구진
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