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Cancer-derived extracellular vesicles: function and clinical applications in prostate cancer

Project Title: „Cancer-derived extracellular vesicles: function and clinical applications in prostate cancer

Funding: EEA and Norwegian Financial Mechanisms 2009-2014 Programme LV05 “Research and Scholarships”  

Project No.: NFI/R/2014/045

Period: 24 month (1st May 2015–30st April 2017)

Partners: Oslo University Hospital (OUH); University of Latvia, Faculty of Medicine (LU MF)

 

 

Project costs: 486 485,00 EUR (BMC – 252 720,00 EUR; OUH – 187 012,00 EUR; LU MF – 46 753,00 EUR)

Principle Investigator: Dr.biol. A.Linē

Contacts:

Project Investigator, Coordinator Dr.biol. Aija Linē (BMC) - aija@biomed.lu.lv

WP leader and Member of Steering Committee Dr. Alicia Llorente (OUH) - alillo@rr-research.no 

WP leader and Member of Steering Committee Dr.biol. Una Riekstiņa (LU MF) - una.riekstina@lu.lv 

Project Manager (BMC) – liga.vonda@biomed.lu.lv 

 

Extracellular vesicles (EVs) have recently emerged as important mediators of intercellular communication and been implicated in the regulation of physiological and pathological processes, including cancer. Cancer-derived EVs contain disease-related molecules, and therefore EVs in biological fluids may serve as a “liquid biopsy” enabling patient stratification and monitoring of treatment response. In addition, molecular analysis of cancer-derived EVs may provide novel insights into how cancer cells and tumour-host communicate and drive cancer progression. Importantly, this may lead to the discovery of novel targets for therapeutic intervention. The overall objective of this project is to delineate the role of cancer-derived EVs in the progression of prostate cancer (PC) and to identify EV-enclosed small RNAs associated with cancer aggressiveness that can serve as potential therapeutic targets and/or prognostic biomarkers of prostate cancer.

 

The Project consists of following work packages:

  1.  Characterisation and comparison of EV subpopulations released by aggressive and indolent PC cells;
  2.  EV uptake by various recipient cells;
  3.  Studies of biodistribution of PC-derived EVs and their impact on tumour growth and anti-tumour immune response using a mouse model of PC;
  4.  Collection of prostate cancer clinical material;
  5.  Analysis of RNA-biomarker candidates in biofluids of PC patients.

 

 

Progress of the project

Achievements:

  • A review on Diagnostic, prognostic and predictive value of cell-free miRNAs in prostate cancer is published in Molecular Cancer (IF=5.888).
  • The results on the role of hypoxic EVs in the intercellular communication among cancer cells were presented at the ISEV2016 meeting in Rotterdam.

 

August – October

  • The initial RNA sequencing results were obtained from the plasma and urinary EVs collected before and after the surgery and the tumour tissue of a single PC patient. These data for the first time allowed to compare the RNA content in plasma and urinary EVs, to assess how the RNA content is affected by the surgery and to identify cancer-associated RNAs.
  • The collection of clinical data and follow-up information for the retrospective PC and BPH cohort was started.
  • The generation of EV reports for the biodistribution studies was continued.
  • The analysis of miRNA biomarkers in the retrospective PC and BPH cohort was started.

 

May - July:

  • As the initial results of the pilot study on deep sequencing of RNA from urinary EVs obtained at OUH were promising, Cristina Bajo Santos attended OUH in order to continue the work on the deep sequencing of urinary EVs from a larger cohort of PC patients.
  • Kristīne Soboļevska successfully defended her course paper on the fractionation and characterisation of EV subpopulations in urine (under supervision of Cristina Bajo Santos).
  • The enrolment of new patients in the prospective longitudinal study was completed and the collection of clinical samples at 3 and 9 month time points is ongoing.
  • The strategy for generating EV reporters was changed: a set of new CD63-Strep Tag fusion constructs was obtained and the conditions of transfections are being optimised.

 

February - April:

  • PhD students Lilite Sadovska and Juris Stefanovičs completed their training at OUH and Oslo University. Lilite Sadovska acquired experience in the generation of xenograft tumour models in mice, while Juris Stefanovičs was working on the immune-isolation of EVs from PC patients’ biofluids.
  • The work on the fractionation of EVs and characterisation of EV subpopulations is ongoing.
  • Patient enrolment in the prospective longitudinal study and sample collection is ongoing.
  • Generation of EV reporters and selection of stably transfected mouse prostate cancer cell clones is in progress.
  • Analysis of miRNA content in various EV subpopulations in plasma and urine of PC patients is in progress.

 

November - January

  • Within the framework of the Fellowship activity, PhD students Lilite Sadovska and Juris Stefanovčs are undertaking a study period at the OUH to acquire experience in mouse models of cancer and to develop novel techniques for the isolation of EVs from biofluids of prostate cancer patients.
  • Patient enrolment and sample collection is ongoing.
  • Generation of EV reporters and selection of stably transfected mouse prostate cancer cells is in progress.
  • Analysis of miRNA content in various EV subpopulations in plasma and urine of PC patients is in progress.

 

 

Lilite Sadovska is undergoing training in Translational Cancer Therapy lab headed by Dr. Dr. Kjersti Flatmark. From the left: Dr. Markus Fusser, Lilite Sadovska, Dr. Kjersti Flatmark, Dr. Stein Waagene.

The project meeting where the participants discussed the obtained results and challenges and set the tasks for the next period.




Mājas lapas izstrādi finansēja ERAF 2.1.1.2. aktivitātes projekts Nr. 2010/0196/2DP/2.1.1.2.0/10/APIA/VIAA/004 "Latvijas biomedicīnas pētījumu integrācija Eiropas zinātnes telpā".