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Lipidome-based Targeting of STAT3-driven Breast Cancer Cells Using Poly-l-glutamic Acid-coated Layer-by-Layer
Isidora Tošić1,2,3, Lisa N Heppler1,2, Susana P Egusquiaguirre1
1Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts.
Abstract:
The oncogenic transcription factor STAT3 is aberrantly activated in 70% of breast cancers, including nearly all triple-negative breast cancers (TNBCs). Because STAT3 is difficult to target directly, we considered whether metabolic changes driven by activated STAT3 could provide a therapeutic opportunity. We found that STAT3 prominently modulated several lipid classes, with most profound effects on N-acyl taurine and arachidonic acid, both of which are involved in plasma membrane remodeling. To exploit these metabolic changes therapeutically, we screened a library of layer-by-layer (LbL) nanoparticles (NPs) differing in the surface layer that modulates interactivity with the cell membrane. We found that poly-l-glutamic acid (PLE)-coated NPs bind to STAT3-transformed breast cancer cells with 50% greater efficiency than to nontransformed cells, and the heightened PLE-NP binding to TNBC cells was attenuated by STAT3 inhibition. This effect was also observed in densely packed three-dimensional breast cancer organoids. As STAT3-transformed cells show greater resistance to cytotoxic agents, we evaluated whether enhanced targeted delivery via PLE-NPs would provide a therapeutic advantage. We found that cisplatin-loaded PLE-NPs induced apoptosis of STAT3-driven cells at lower doses compared with both unencapsulated cisplatin and cisplatin-loaded nontargeted NPs. In addition, because radiation is commonly used in breast cancer treatment, and may alter cellular lipid distribution, we analyzed its effect on PLE-NP-cell binding. Irradiation of cells enhanced the STAT3-targeting properties of PLE-NPs in a dose-dependent manner, suggesting potential synergies between these therapeutic modalities. These findings suggest that cellular lipid changes driven by activated STAT3 may be exploited therapeutically using unique LbL NPs.
Insights
Activated STAT3 in breast cancer alters cell lipids, creating a therapeutic target. Poly-l-glutamic acid nanoparticles effectively target these STAT3-driven cancer cells, enhancing drug delivery and potentially synergizing with radiation therapy.
Area of Science:
- Oncology
- Biochemistry
- Nanotechnology
Background:
- Signal transducer and activator of transcription 3 (STAT3) is a key oncogenic factor in breast cancer, particularly triple-negative breast cancer (TNBC).
- STAT3 dysregulation drives metabolic alterations, including changes in lipid metabolism, which are not directly targetable.
- These STAT3-induced metabolic shifts, especially in N-acyl taurine and arachidonic acid, impact plasma membrane remodeling and offer a potential therapeutic vulnerability.
Purpose of the Study:
- To investigate if STAT3-driven metabolic changes in breast cancer cells can be therapeutically exploited.
- To develop and evaluate targeted nanoparticles (NPs) for delivering therapeutics to STAT3-activated breast cancer cells.
- To assess the potential of these targeted NPs in combination with existing therapies like chemotherapy and radiation.
Main Methods:
- Screening of layer-by-layer (LbL) nanoparticles with varying surface coatings.
- Evaluating the binding efficiency of poly-l-glutamic acid (PLE)-coated NPs to STAT3-transformed breast cancer cells and organoids.
- Assessing the therapeutic efficacy of cisplatin-loaded PLE-NPs in inducing apoptosis in STAT3-driven cells.
- Analyzing the effect of irradiation on PLE-NP binding to cancer cells.
Main Results:
- Poly-l-glutamic acid (PLE)-coated NPs demonstrated significantly higher binding affinity (50% greater) to STAT3-transformed breast cancer cells compared to non-transformed cells.
- This enhanced binding was specific to STAT3 activation and observed in both cell cultures and 3D organoid models.
- Cisplatin-loaded PLE-NPs effectively induced apoptosis in STAT3-driven cells at lower concentrations than unencapsulated cisplatin or non-targeted NPs.
- Irradiation enhanced the targeting capability of PLE-NPs in a dose-dependent manner, suggesting synergistic potential.
Conclusions:
- STAT3-induced alterations in cellular lipid metabolism represent a viable therapeutic target in breast cancer.
- Layer-by-layer (LbL) nanoparticles, specifically PLE-coated NPs, offer a promising strategy for targeted delivery to STAT3-activated breast cancer cells.
- Targeted delivery via PLE-NPs enhances chemotherapeutic efficacy and shows potential for combination therapy with radiation, offering new avenues for TNBC treatment.
