Sofia N Luna, Venu Yakati, Lalita A Shevde, Shreyas S Rao
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引用次数: 0
Abstract
Breast cancer is the most commonly diagnosed cancer and the leading cause of cancer mortality in females. Approximately 20-30% of patients with advanced breast cancer develop brain metastasis. Often, brain metastatic breast cancer (BMBC) exhibits a nonproliferative (dormant) phenotype and therapy resistance due to the unfavorable organ microenvironment. However, the mechanisms by which dormant BMBC micrometastases develop resistance to treatment remain unknown. In the current work, we utilized hyaluronic acid (HA) hydrogels to study the relationship between matrix rigidity-induced dormancy and the drug resistance of BMBC spheroids. BMBC spheroids were cultured on soft (∼0.4 kPa) or stiff (∼4.5 kPa) HA hydrogels, known to induce dormant versus proliferative states, and their response to Paclitaxel (PTX) or Lapatinib (LAP) treatment was measured. Spheroids on soft HA hydrogels were resistant to PTX or LAP treatment. Conversely, spheroids on stiff HA hydrogels were responsive to PTX or LAP treatment. Moreover, the resistance to therapy was mediated by glucocorticoid receptor (GR) signaling via serum/glucocorticoid-regulated kinase 1 (SGK-1) and RANBP1 in triple-negative BMBC cells and β-catenin and GSK-3β in human epidermal growth factor receptor 2 positive (HER2+) BMBC cells. Further, SGK1 inhibition alleviated drug resistance and resulted in response to treatment. Overall, this work provides evidence for dormancy associated drug resistance through GR signaling in BMBC spheroids.
期刊介绍：
ACS Biomaterials Science & Engineering is the leading journal in the field of biomaterials, serving as an international forum for publishing cutting-edge research and innovative ideas on a broad range of topics:
Applications and Health – implantable tissues and devices, prosthesis, health risks, toxicology
Bio-interactions and Bio-compatibility – material-biology interactions, chemical/morphological/structural communication, mechanobiology, signaling and biological responses, immuno-engineering, calcification, coatings, corrosion and degradation of biomaterials and devices, biophysical regulation of cell functions
Characterization, Synthesis, and Modification – new biomaterials, bioinspired and biomimetic approaches to biomaterials, exploiting structural hierarchy and architectural control, combinatorial strategies for biomaterials discovery, genetic biomaterials design, synthetic biology, new composite systems, bionics, polymer synthesis
Controlled Release and Delivery Systems – biomaterial-based drug and gene delivery, bio-responsive delivery of regulatory molecules, pharmaceutical engineering
Healthcare Advances – clinical translation, regulatory issues, patient safety, emerging trends
Imaging and Diagnostics – imaging agents and probes, theranostics, biosensors, monitoring
Manufacturing and Technology – 3D printing, inks, organ-on-a-chip, bioreactor/perfusion systems, microdevices, BioMEMS, optics and electronics interfaces with biomaterials, systems integration
Modeling and Informatics Tools – scaling methods to guide biomaterial design, predictive algorithms for structure-function, biomechanics, integrating bioinformatics with biomaterials discovery, metabolomics in the context of biomaterials
Tissue Engineering and Regenerative Medicine – basic and applied studies, cell therapies, scaffolds, vascularization, bioartificial organs, transplantation and functionality, cellular agriculture
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