Radiation induces ESCRT pathway dependent CD44v3+ extracellular vesicle production stimulating pro-tumor fibroblast activity in breast cancer
Despite recent advances in radiotherapeutic strategies, acquired resistance remains a major obstacle, leading to tumor recurrence for many patients. Once thought to be a strictly cancer cell intrinsic property, it is becoming increasingly clear that treatment-resistance is driven in part by complex...
| Main Authors: | , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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Frontiers Media S.A.
2022-08-01
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| Series: | Frontiers in Oncology |
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| Online Access: | https://www.frontiersin.org/articles/10.3389/fonc.2022.913656/full |
| _version_ | 1811183067295907840 |
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| author | Gene Chatman Clark Gene Chatman Clark James David Hampton James David Hampton Jennifer E. Koblinski Jennifer E. Koblinski Bridget Quinn Bridget Quinn Sitara Mahmoodi Olga Metcalf Chunqing Guo Chunqing Guo Chunqing Guo Erica Peterson Erica Peterson Paul B. Fisher Paul B. Fisher Paul B. Fisher Paul B. Fisher Nicholas P. Farrell Nicholas P. Farrell Nicholas P. Farrell Xiang-Yang Wang Xiang-Yang Wang Xiang-Yang Wang Xiang-Yang Wang Ross B. Mikkelsen Ross B. Mikkelsen |
| author_facet | Gene Chatman Clark Gene Chatman Clark James David Hampton James David Hampton Jennifer E. Koblinski Jennifer E. Koblinski Bridget Quinn Bridget Quinn Sitara Mahmoodi Olga Metcalf Chunqing Guo Chunqing Guo Chunqing Guo Erica Peterson Erica Peterson Paul B. Fisher Paul B. Fisher Paul B. Fisher Paul B. Fisher Nicholas P. Farrell Nicholas P. Farrell Nicholas P. Farrell Xiang-Yang Wang Xiang-Yang Wang Xiang-Yang Wang Xiang-Yang Wang Ross B. Mikkelsen Ross B. Mikkelsen |
| author_sort | Gene Chatman Clark |
| collection | DOAJ |
| description | Despite recent advances in radiotherapeutic strategies, acquired resistance remains a major obstacle, leading to tumor recurrence for many patients. Once thought to be a strictly cancer cell intrinsic property, it is becoming increasingly clear that treatment-resistance is driven in part by complex interactions between cancer cells and non-transformed cells of the tumor microenvironment. Herein, we report that radiotherapy induces the production of extracellular vesicles by breast cancer cells capable of stimulating tumor-supporting fibroblast activity, facilitating tumor survival and promoting cancer stem-like cell expansion. This pro-tumor activity was associated with fibroblast production of the paracrine signaling factor IL-6 and was dependent on the expression of the heparan sulfate proteoglycan CD44v3 on the vesicle surface. Enzymatic removal or pharmaceutical inhibition of its heparan sulfate side chains disrupted this tumor-fibroblast crosstalk. Additionally, we show that the radiation-induced production of CD44v3+ vesicles is effectively silenced by blocking the ESCRT pathway using a soluble pharmacological inhibitor of MDA-9/Syntenin/SDCBP PDZ1 domain activity, PDZ1i. This population of vesicles was also detected in the sera of human patients undergoing radiotherapy, therefore representing a potential biomarker for radiation therapy and providing an opportunity for clinical intervention to improve treatment outcomes. |
| first_indexed | 2024-04-11T09:41:32Z |
| format | Article |
| id | doaj.art-f282329de9d04973b8f6e3130a15ad63 |
| institution | Directory Open Access Journal |
| issn | 2234-943X |
| language | English |
| last_indexed | 2024-04-11T09:41:32Z |
| publishDate | 2022-08-01 |
| publisher | Frontiers Media S.A. |
| record_format | Article |
| series | Frontiers in Oncology |
| spelling | doaj.art-f282329de9d04973b8f6e3130a15ad632022-12-22T04:31:11ZengFrontiers Media S.A.Frontiers in Oncology2234-943X2022-08-011210.3389/fonc.2022.913656913656Radiation induces ESCRT pathway dependent CD44v3+ extracellular vesicle production stimulating pro-tumor fibroblast activity in breast cancerGene Chatman Clark0Gene Chatman Clark1James David Hampton2James David Hampton3Jennifer E. Koblinski4Jennifer E. Koblinski5Bridget Quinn6Bridget Quinn7Sitara Mahmoodi8Olga Metcalf9Chunqing Guo10Chunqing Guo11Chunqing Guo12Erica Peterson13Erica Peterson14Paul B. Fisher15Paul B. Fisher16Paul B. Fisher17Paul B. Fisher18Nicholas P. Farrell19Nicholas P. Farrell20Nicholas P. Farrell21Xiang-Yang Wang22Xiang-Yang Wang23Xiang-Yang Wang24Xiang-Yang Wang25Ross B. Mikkelsen26Ross B. Mikkelsen27Virginia Commonwealth University, Richmond, VA, United StatesDepartment of Biochemistry, Virginia Commonwealth University, Richmond, VA, United StatesVirginia Commonwealth University, Richmond, VA, United StatesDepartment of Biochemistry, Virginia Commonwealth University, Richmond, VA, United StatesVirginia Commonwealth University, Richmond, VA, United StatesDepartment of Pathology, Virginia Commonwealth University, Richmond, VA, United StatesVirginia Commonwealth University, Richmond, VA, United StatesDepartment of Radiation Oncology, Virginia Commonwealth University, Richmond, VA, United StatesVirginia Commonwealth University, Richmond, VA, United StatesUniversity of Virginia, Charlottesville, VA, United StatesVirginia Commonwealth University, Richmond, VA, United StatesDepartment of Human Molecular Genetics, Virginia Commonwealth University, Richmond, VA, United StatesVCU Massey Cancer Center, Virginia Commonwealth University, Richmond, VA, United StatesVirginia Commonwealth University, Richmond, VA, United StatesVCU Massey Cancer Center, Virginia Commonwealth University, Richmond, VA, United StatesVirginia Commonwealth University, Richmond, VA, United StatesDepartment of Human Molecular Genetics, Virginia Commonwealth University, Richmond, VA, United StatesVCU Massey Cancer Center, Virginia Commonwealth University, Richmond, VA, United StatesVirginia Commonwealth University (VCU) Institute of Molecular Medicine, Virginia Commonwealth University, Richmond, VA, United StatesVirginia Commonwealth University, Richmond, VA, United StatesVCU Massey Cancer Center, Virginia Commonwealth University, Richmond, VA, United StatesDepartment of Chemistry, Virginia Commonwealth University, Richmond, VA, United StatesVirginia Commonwealth University, Richmond, VA, United StatesUniversity of Virginia, Charlottesville, VA, United StatesVCU Massey Cancer Center, Virginia Commonwealth University, Richmond, VA, United StatesVirginia Commonwealth University (VCU) Institute of Molecular Medicine, Virginia Commonwealth University, Richmond, VA, United StatesVirginia Commonwealth University, Richmond, VA, United StatesDepartment of Radiation Oncology, Virginia Commonwealth University, Richmond, VA, United StatesDespite recent advances in radiotherapeutic strategies, acquired resistance remains a major obstacle, leading to tumor recurrence for many patients. Once thought to be a strictly cancer cell intrinsic property, it is becoming increasingly clear that treatment-resistance is driven in part by complex interactions between cancer cells and non-transformed cells of the tumor microenvironment. Herein, we report that radiotherapy induces the production of extracellular vesicles by breast cancer cells capable of stimulating tumor-supporting fibroblast activity, facilitating tumor survival and promoting cancer stem-like cell expansion. This pro-tumor activity was associated with fibroblast production of the paracrine signaling factor IL-6 and was dependent on the expression of the heparan sulfate proteoglycan CD44v3 on the vesicle surface. Enzymatic removal or pharmaceutical inhibition of its heparan sulfate side chains disrupted this tumor-fibroblast crosstalk. Additionally, we show that the radiation-induced production of CD44v3+ vesicles is effectively silenced by blocking the ESCRT pathway using a soluble pharmacological inhibitor of MDA-9/Syntenin/SDCBP PDZ1 domain activity, PDZ1i. This population of vesicles was also detected in the sera of human patients undergoing radiotherapy, therefore representing a potential biomarker for radiation therapy and providing an opportunity for clinical intervention to improve treatment outcomes.https://www.frontiersin.org/articles/10.3389/fonc.2022.913656/fullcancer associated fibroblasts (CAF)cancer stem cell (CSC)extracurricular vesicles (EVs)radiotherapyradioresistanceESCRT pathway |
| spellingShingle | Gene Chatman Clark Gene Chatman Clark James David Hampton James David Hampton Jennifer E. Koblinski Jennifer E. Koblinski Bridget Quinn Bridget Quinn Sitara Mahmoodi Olga Metcalf Chunqing Guo Chunqing Guo Chunqing Guo Erica Peterson Erica Peterson Paul B. Fisher Paul B. Fisher Paul B. Fisher Paul B. Fisher Nicholas P. Farrell Nicholas P. Farrell Nicholas P. Farrell Xiang-Yang Wang Xiang-Yang Wang Xiang-Yang Wang Xiang-Yang Wang Ross B. Mikkelsen Ross B. Mikkelsen Radiation induces ESCRT pathway dependent CD44v3+ extracellular vesicle production stimulating pro-tumor fibroblast activity in breast cancer Frontiers in Oncology cancer associated fibroblasts (CAF) cancer stem cell (CSC) extracurricular vesicles (EVs) radiotherapy radioresistance ESCRT pathway |
| title | Radiation induces ESCRT pathway dependent CD44v3+ extracellular vesicle production stimulating pro-tumor fibroblast activity in breast cancer |
| title_full | Radiation induces ESCRT pathway dependent CD44v3+ extracellular vesicle production stimulating pro-tumor fibroblast activity in breast cancer |
| title_fullStr | Radiation induces ESCRT pathway dependent CD44v3+ extracellular vesicle production stimulating pro-tumor fibroblast activity in breast cancer |
| title_full_unstemmed | Radiation induces ESCRT pathway dependent CD44v3+ extracellular vesicle production stimulating pro-tumor fibroblast activity in breast cancer |
| title_short | Radiation induces ESCRT pathway dependent CD44v3+ extracellular vesicle production stimulating pro-tumor fibroblast activity in breast cancer |
| title_sort | radiation induces escrt pathway dependent cd44v3 extracellular vesicle production stimulating pro tumor fibroblast activity in breast cancer |
| topic | cancer associated fibroblasts (CAF) cancer stem cell (CSC) extracurricular vesicles (EVs) radiotherapy radioresistance ESCRT pathway |
| url | https://www.frontiersin.org/articles/10.3389/fonc.2022.913656/full |
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