Extracellular Hsp90 Binds to and Aligns Collagen-1 to Enhance Breast Cancer Cell Invasiveness
Cancer cell-secreted eHsp90 binds and activates proteins in the tumor microenvironment crucial in cancer invasion. Therefore, targeting eHsp90 could inhibit invasion, preventing metastasis—the leading cause of cancer-related mortality. Previous eHsp90 studies have solely focused on its rol...
| Main Authors: | , , , , |
|---|---|
| 格式: | 文件 |
| 出版: |
Multidisciplinary Digital Publishing Institute
2023
|
| 在线阅读: | https://hdl.handle.net/1721.1/152943 |
| _version_ | 1826216248263835648 |
|---|---|
| author | Singh, Pragya Ramanathan, Varshini Zhang, Yang Georgakoudi, Irene Jay, Daniel G. |
| author_facet | Singh, Pragya Ramanathan, Varshini Zhang, Yang Georgakoudi, Irene Jay, Daniel G. |
| author_sort | Singh, Pragya |
| collection | MIT |
| description | Cancer cell-secreted eHsp90 binds and activates proteins in the tumor microenvironment crucial in cancer invasion. Therefore, targeting eHsp90 could inhibit invasion, preventing metastasis—the leading cause of cancer-related mortality. Previous eHsp90 studies have solely focused on its role in cancer invasion through the 2D basement membrane (BM), a form of extracellular matrix (ECM) that lines the epithelial compartment. However, its role in cancer invasion through the 3D Interstitial Matrix (IM), an ECM beyond the BM, remains unexplored. Using a Collagen-1 binding assay and second harmonic generation (SHG) imaging, we demonstrate that eHsp90 directly binds and aligns Collagen-1 fibers, the primary component of IM. Furthermore, we show that eHsp90 enhances Collagen-1 invasion of breast cancer cells in the Transwell assay. Using Hsp90 conformation mutants and inhibitors, we established that the Hsp90 dimer binds to Collagen-1 via its N-domain. We also demonstrated that while Collagen-1 binding and alignment are not influenced by Hsp90’s ATPase activity attributed to the N-domain, its open conformation is crucial for increasing Collagen-1 alignment and promoting breast cancer cell invasion. These findings unveil a novel role for eHsp90 in invasion through the IM and offer valuable mechanistic insights into potential therapeutic approaches for inhibiting Hsp90 to suppress invasion and metastasis. |
| first_indexed | 2024-09-23T16:44:40Z |
| format | Article |
| id | mit-1721.1/152943 |
| institution | Massachusetts Institute of Technology |
| last_indexed | 2024-09-23T16:44:40Z |
| publishDate | 2023 |
| publisher | Multidisciplinary Digital Publishing Institute |
| record_format | dspace |
| spelling | mit-1721.1/1529432023-11-14T03:01:50Z Extracellular Hsp90 Binds to and Aligns Collagen-1 to Enhance Breast Cancer Cell Invasiveness Singh, Pragya Ramanathan, Varshini Zhang, Yang Georgakoudi, Irene Jay, Daniel G. Cancer cell-secreted eHsp90 binds and activates proteins in the tumor microenvironment crucial in cancer invasion. Therefore, targeting eHsp90 could inhibit invasion, preventing metastasis—the leading cause of cancer-related mortality. Previous eHsp90 studies have solely focused on its role in cancer invasion through the 2D basement membrane (BM), a form of extracellular matrix (ECM) that lines the epithelial compartment. However, its role in cancer invasion through the 3D Interstitial Matrix (IM), an ECM beyond the BM, remains unexplored. Using a Collagen-1 binding assay and second harmonic generation (SHG) imaging, we demonstrate that eHsp90 directly binds and aligns Collagen-1 fibers, the primary component of IM. Furthermore, we show that eHsp90 enhances Collagen-1 invasion of breast cancer cells in the Transwell assay. Using Hsp90 conformation mutants and inhibitors, we established that the Hsp90 dimer binds to Collagen-1 via its N-domain. We also demonstrated that while Collagen-1 binding and alignment are not influenced by Hsp90’s ATPase activity attributed to the N-domain, its open conformation is crucial for increasing Collagen-1 alignment and promoting breast cancer cell invasion. These findings unveil a novel role for eHsp90 in invasion through the IM and offer valuable mechanistic insights into potential therapeutic approaches for inhibiting Hsp90 to suppress invasion and metastasis. 2023-11-13T19:50:46Z 2023-11-13T19:50:46Z 2023-10-31 2023-11-10T14:58:03Z Article http://purl.org/eprint/type/JournalArticle https://hdl.handle.net/1721.1/152943 Cancers 15 (21): 5237 (2023) PUBLISHER_CC http://dx.doi.org/10.3390/cancers15215237 Creative Commons Attribution https://creativecommons.org/licenses/by/4.0/ application/pdf Multidisciplinary Digital Publishing Institute Multidisciplinary Digital Publishing Institute |
| spellingShingle | Singh, Pragya Ramanathan, Varshini Zhang, Yang Georgakoudi, Irene Jay, Daniel G. Extracellular Hsp90 Binds to and Aligns Collagen-1 to Enhance Breast Cancer Cell Invasiveness |
| title | Extracellular Hsp90 Binds to and Aligns Collagen-1 to Enhance Breast Cancer Cell Invasiveness |
| title_full | Extracellular Hsp90 Binds to and Aligns Collagen-1 to Enhance Breast Cancer Cell Invasiveness |
| title_fullStr | Extracellular Hsp90 Binds to and Aligns Collagen-1 to Enhance Breast Cancer Cell Invasiveness |
| title_full_unstemmed | Extracellular Hsp90 Binds to and Aligns Collagen-1 to Enhance Breast Cancer Cell Invasiveness |
| title_short | Extracellular Hsp90 Binds to and Aligns Collagen-1 to Enhance Breast Cancer Cell Invasiveness |
| title_sort | extracellular hsp90 binds to and aligns collagen 1 to enhance breast cancer cell invasiveness |
| url | https://hdl.handle.net/1721.1/152943 |
| work_keys_str_mv | AT singhpragya extracellularhsp90bindstoandalignscollagen1toenhancebreastcancercellinvasiveness AT ramanathanvarshini extracellularhsp90bindstoandalignscollagen1toenhancebreastcancercellinvasiveness AT zhangyang extracellularhsp90bindstoandalignscollagen1toenhancebreastcancercellinvasiveness AT georgakoudiirene extracellularhsp90bindstoandalignscollagen1toenhancebreastcancercellinvasiveness AT jaydanielg extracellularhsp90bindstoandalignscollagen1toenhancebreastcancercellinvasiveness |