Lipidome-based Targeting of STAT3-driven Breast Cancer Cells Using Poly-l-glutamic Acid–coated Layer-by-Layer Nanoparticles
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 opportu...
| Main Authors: | , , , , , , , , , , , , , |
|---|---|
| Other Authors: | |
| Format: | Article |
| Language: | English |
| Published: |
American Association for Cancer Research (AACR)
2021
|
| Online Access: | https://hdl.handle.net/1721.1/132701 |
| _version_ | 1826206627791896576 |
|---|---|
| author | Tošić, Isidora Heppler, Lisa N Egusquiaguirre, Susana P Boehnke, Natalie Correa, Santiago Costa, Daniel F Moore, Elizabeth A Grossman Pal, Sharmistha Richardson, Douglas S Ivanov, Alexander R Haas-Kogan, Daphne A Nomura, Daniel K Hammond, Paula T Frank, David A |
| author2 | Koch Institute for Integrative Cancer Research at MIT |
| author_facet | Koch Institute for Integrative Cancer Research at MIT Tošić, Isidora Heppler, Lisa N Egusquiaguirre, Susana P Boehnke, Natalie Correa, Santiago Costa, Daniel F Moore, Elizabeth A Grossman Pal, Sharmistha Richardson, Douglas S Ivanov, Alexander R Haas-Kogan, Daphne A Nomura, Daniel K Hammond, Paula T Frank, David A |
| author_sort | Tošić, Isidora |
| collection | MIT |
| description | 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. |
| first_indexed | 2024-09-23T13:35:35Z |
| format | Article |
| id | mit-1721.1/132701 |
| institution | Massachusetts Institute of Technology |
| language | English |
| last_indexed | 2024-09-23T13:35:35Z |
| publishDate | 2021 |
| publisher | American Association for Cancer Research (AACR) |
| record_format | dspace |
| spelling | mit-1721.1/1327012024-05-31T20:21:09Z Lipidome-based Targeting of STAT3-driven Breast Cancer Cells Using Poly-l-glutamic Acid–coated Layer-by-Layer Nanoparticles Tošić, Isidora Heppler, Lisa N Egusquiaguirre, Susana P Boehnke, Natalie Correa, Santiago Costa, Daniel F Moore, Elizabeth A Grossman Pal, Sharmistha Richardson, Douglas S Ivanov, Alexander R Haas-Kogan, Daphne A Nomura, Daniel K Hammond, Paula T Frank, David A Koch Institute for Integrative Cancer Research at MIT Massachusetts Institute of Technology. Department of Chemical Engineering Massachusetts Institute of Technology. Institute for Soldier Nanotechnologies 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. 2021-10-04T18:23:32Z 2021-10-04T18:23:32Z 2021-02 2021-01 2021-10-04T16:47:48Z Article http://purl.org/eprint/type/JournalArticle 1535-7163 1538-8514 https://hdl.handle.net/1721.1/132701 Tošić, Isidora, Heppler, Lisa N, Egusquiaguirre, Susana P, Boehnke, Natalie, Correa, Santiago et al. 2021. "Lipidome-based Targeting of STAT3-driven Breast Cancer Cells Using Poly-l-glutamic Acid–coated Layer-by-Layer Nanoparticles." Molecular Cancer Therapeutics, 20 (4). en 10.1158/1535-7163.MCT-20-0505 Molecular Cancer Therapeutics Creative Commons Attribution-Noncommercial-Share Alike http://creativecommons.org/licenses/by-nc-sa/4.0/ application/pdf American Association for Cancer Research (AACR) PMC |
| spellingShingle | Tošić, Isidora Heppler, Lisa N Egusquiaguirre, Susana P Boehnke, Natalie Correa, Santiago Costa, Daniel F Moore, Elizabeth A Grossman Pal, Sharmistha Richardson, Douglas S Ivanov, Alexander R Haas-Kogan, Daphne A Nomura, Daniel K Hammond, Paula T Frank, David A Lipidome-based Targeting of STAT3-driven Breast Cancer Cells Using Poly-l-glutamic Acid–coated Layer-by-Layer Nanoparticles |
| title | Lipidome-based Targeting of STAT3-driven Breast Cancer Cells Using Poly-l-glutamic Acid–coated Layer-by-Layer Nanoparticles |
| title_full | Lipidome-based Targeting of STAT3-driven Breast Cancer Cells Using Poly-l-glutamic Acid–coated Layer-by-Layer Nanoparticles |
| title_fullStr | Lipidome-based Targeting of STAT3-driven Breast Cancer Cells Using Poly-l-glutamic Acid–coated Layer-by-Layer Nanoparticles |
| title_full_unstemmed | Lipidome-based Targeting of STAT3-driven Breast Cancer Cells Using Poly-l-glutamic Acid–coated Layer-by-Layer Nanoparticles |
| title_short | Lipidome-based Targeting of STAT3-driven Breast Cancer Cells Using Poly-l-glutamic Acid–coated Layer-by-Layer Nanoparticles |
| title_sort | lipidome based targeting of stat3 driven breast cancer cells using poly l glutamic acid coated layer by layer nanoparticles |
| url | https://hdl.handle.net/1721.1/132701 |
| work_keys_str_mv | AT tosicisidora lipidomebasedtargetingofstat3drivenbreastcancercellsusingpolylglutamicacidcoatedlayerbylayernanoparticles AT hepplerlisan lipidomebasedtargetingofstat3drivenbreastcancercellsusingpolylglutamicacidcoatedlayerbylayernanoparticles AT egusquiaguirresusanap lipidomebasedtargetingofstat3drivenbreastcancercellsusingpolylglutamicacidcoatedlayerbylayernanoparticles AT boehnkenatalie lipidomebasedtargetingofstat3drivenbreastcancercellsusingpolylglutamicacidcoatedlayerbylayernanoparticles AT correasantiago lipidomebasedtargetingofstat3drivenbreastcancercellsusingpolylglutamicacidcoatedlayerbylayernanoparticles AT costadanielf lipidomebasedtargetingofstat3drivenbreastcancercellsusingpolylglutamicacidcoatedlayerbylayernanoparticles AT mooreelizabethagrossman lipidomebasedtargetingofstat3drivenbreastcancercellsusingpolylglutamicacidcoatedlayerbylayernanoparticles AT palsharmistha lipidomebasedtargetingofstat3drivenbreastcancercellsusingpolylglutamicacidcoatedlayerbylayernanoparticles AT richardsondouglass lipidomebasedtargetingofstat3drivenbreastcancercellsusingpolylglutamicacidcoatedlayerbylayernanoparticles AT ivanovalexanderr lipidomebasedtargetingofstat3drivenbreastcancercellsusingpolylglutamicacidcoatedlayerbylayernanoparticles AT haaskogandaphnea lipidomebasedtargetingofstat3drivenbreastcancercellsusingpolylglutamicacidcoatedlayerbylayernanoparticles AT nomuradanielk lipidomebasedtargetingofstat3drivenbreastcancercellsusingpolylglutamicacidcoatedlayerbylayernanoparticles AT hammondpaulat lipidomebasedtargetingofstat3drivenbreastcancercellsusingpolylglutamicacidcoatedlayerbylayernanoparticles AT frankdavida lipidomebasedtargetingofstat3drivenbreastcancercellsusingpolylglutamicacidcoatedlayerbylayernanoparticles |