2. Academic Validation
  3. Radiation induces ESCRT pathway dependent CD44v3+ extracellular vesicle production stimulating pro-tumor fibroblast activity in breast cancer

Radiation induces ESCRT pathway dependent CD44v3+ extracellular vesicle production stimulating pro-tumor fibroblast activity in breast cancer

  • Front Oncol. 2022 Aug 29:12:913656. doi: 10.3389/fonc.2022.913656.
Gene Chatman Clark 1 2,  James David Hampton 1 2,  Jennifer E Koblinski 1 3,  Bridget Quinn 1 4,  Sitara Mahmoodi 1,  Olga Metcalf 5,  Chunqing Guo 1 6 7,  Erica Peterson 1 7,  Paul B Fisher 1 6 7 8,  Nicholas P Farrell 1 7 9,  Xiang-Yang Wang 1 5 7 8,  Ross B Mikkelsen 1 4
Affiliations

Affiliations

  • 1 Virginia Commonwealth University, Richmond, VA, United States.
  • 2 Department of Biochemistry, Virginia Commonwealth University, Richmond, VA, United States.
  • 3 Department of Pathology, Virginia Commonwealth University, Richmond, VA, United States.
  • 4 Department of Radiation Oncology, Virginia Commonwealth University, Richmond, VA, United States.
  • 5 University of Virginia, Charlottesville, VA, United States.
  • 6 Department of Human Molecular Genetics, Virginia Commonwealth University, Richmond, VA, United States.
  • 7 VCU Massey Cancer Center, Virginia Commonwealth University, Richmond, VA, United States.
  • 8 Virginia Commonwealth University (VCU) Institute of Molecular Medicine, Virginia Commonwealth University, Richmond, VA, United States.
  • 9 Department of Chemistry, Virginia Commonwealth University, Richmond, VA, United States.
PMID: 36106109 DOI: 10.3389/fonc.2022.913656
Abstract

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.

Keywords

CD44; ESCRT pathway; cancer associated fibroblasts (CAF); cancer stem cell (CSC); extracurricular vesicles (EVs); heparan sulfate (HS); radioresistance; radiotherapy.

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