Periodic Reporting for period 1 - proEVLifeCycle (The life cycle of extracellular vesicles in prostate cancer: from biogenesis and homing, to functional relevance)
Reporting period: 2019-10-01 to 2021-09-30
In the past decade, it has become evident that cancer cells communicate with their environment via very small vesicles (~100 nm; 1000 times thinner than human hair), named extracellular vesicles (EVs). The cancer cells themselves and the normal cells within and surrounding the tumor secrete these EVs and likely create an environment which is optimal for the cancer to survive and grow. The lifecycle of EVs is poorly understood and their potential as non-invasive biomarkers and therapy target/agents, a growing area of interest.
PCa is a major global healthcare problem, and equally so within Europe where we see approximately 365,000 new cases and 78,000 deaths each year. Our proEVLifeCycle research will address the high need for novel biomarkers and therapy targets for PCa. Any relief in the burden of this disease will have major impact on the huge socio-economic problems for patients, families, caregivers and society.
The ambitious scientific objectives are to unravel the mysteries of EV biogenesis, homing and uptake to explain how vesicles operate in disease processes; their heterogeneity, their molecular complexity, the biological functions they drive, their local and systemic dissemination and how these may be manipulated. Using state-of-the-art, network-wide shared model systems, imaging, profiling tools and systems biology, the program will enlighten the lifecycle of EVs and identify novel EV biomarkers and PCa therapy targets to address the unmet clinical needs.
Our network of 8 academic and 2 company beneficiaries and 9 partners, provides optimal scientific training, cross-sectoral awareness, entrepreneurship skills, communication in the modern age, extensive opportunities for mobility and patient-facing experiences. We will address the EU-skills gaps by providing well-rounded and inventive experts primed for influential careers, contributing to patient well-being and economic prosperity within the EU.
To unravel how EVs are made by cancer cells and how they find their way to other cells in the tumor and other parts of the body, various model systems have been created including (i) PCa cells growing outside the tumor, (ii) drug screening systems to find inhibitors of EV biogenesis and uptake, (iii) a synthetic EV delivery system to carry chemo to the tumor, and (iv) zebrafish and mouse models to track how EVs travel through an organism. The PCa cells growing outside the tumor are being used to find out which proteins in the cancer cells are involved in making EVs and how EVs can travel through a layer of tightly packed cells that form a barrier. The first results already indicated which proteins play a role in EV biogenesis and which cells in zebrafish and mice take up cancer-derived EVs.
With respect to utilizing EVs from urine, blood and saliva as PCa biomarkers, the molecular characterisation of EV (sub)populations is focussing on the content of EVs, which includes genetic material (RNA), proteins, and small molecules. The first candidate RNA and protein PCa markers have been discovered.
An additional important aspect is to understand the process of EV uptake by normal cells in the tumor and other parts of the body and the functional effects on these cells. A drug screening for compounds that inhibit EV uptake resulted in novel drug candidates to manipulate this process. The role of PCa EVs in changing the function of normal cells has also identified the first clues how this would benefit the tumor cells to grow better and migrate to other organs to form metastases. This important information is the start for therapy interventions including the use of EVs as drug-carriers to bring chemo specifically to the tumor.
Novel EV technologies and computational biology form the basis of our new discoveries. Besides the novel model systems listed above, new technologies are being developed and implemented to measure the number of EVs and how they are different when secreted by cancer or normal cells. Such new technologies are already being designed into new tests to diagnose PCa from a single drop of urine. The computational biology analyses result in the integration of all our data to make the discovery of novel biomarkers and therapy targets possible.
If successful, the socio-economic impact will be huge as novel PCa biomarker tests and therapeutic treatment options can benefit hundreds of thousands of men diagnosed and troubled with this disease. The impact extends beyond the men affected and concerns their partners, families, caregivers and the medical health system.