Daniel Jay's Biography

• Home
• |
• Register
• |
• Agenda
• |
• Posters
• |
• Exhibition
• |
• Venue
• |
• Short Courses
  • Training Courses
• |
• Posters
• |
• Testimonials
• |
• Media
• |

Extracellular Hsp90 and Exosome Release

Tuesday, 24 March 2015 at 14:30

Add to Calendar ▼2015-03-24 14:30:002015-03-24 15:30:00Europe/LondonExtracellular Hsp90 and Exosome ReleaseSELECTBIOenquiries@selectbiosciences.com

We identified extracellular Hsp90 (eHsp90) as pro-invasive using a FALI-based functional proteomic screen for proteins required for cancer invasiveness and showed that Hsp90 helps in the activation of Matrix Metalloproteinase-2 (MMP2) to facilitate breast cancer invasion.  Since then, many pro-invasive proteins activated by eHsp90 for different cancers have been identified by several labs suggesting that eHsp90 may serve as an activation hub for cancer invasion.  We showed that Hsp90 is released from cancer cells via exosomes and these exosomes enhance invasion in an Hsp-90 dependent manner while Barrott et al. (2013) showed that eHsp90 facilitates uptake of tethered Hsp90 inhibitors suggesting that Hsp90 may be trafficked back into cells.  Together, these observations led us postulate that eHsp90 may act in exosome trafficking.  We tested this notion by treating MDA-MB-231 breast cancer cells in culture with the Hsp90 inhibitors ganetespib or STA-12-7191 (a biotinylated and thus impermeant derivative of ganetespib) and measured the release of exosomes and eHsp90 from these cells.  We had recently shown that STA-12-7191 inhibits cell migration of cancer cells and is 5-fold less toxic to normal cells than ganetespib.  Both of these drug treatments resulted in a 50% reduction in exosomes as assessed by protein concentration and Hsp90 compared to no drug controls indicating that inhibition of Hsp90 is involved in exosome release. These findings support a functional role for Hsp90 in exosome release from cancer cells, a new and important process for the communication of tumors with their extracellular milieu that is known to enhance invasion and metastasis.  The mechanisms of exosome trafficking are poorly understood and these studies suggest that Hsp90 is part of this mechanism.