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The life cycle of extracellular vesicles in prostate cancer: from biogenesis and homing, to functional relevance

Periodic Reporting for period 2 - proEVLifeCycle (The life cycle of extracellular vesicles in prostate cancer: from biogenesis and homing, to functional relevance)

Reporting period: 2021-10-01 to 2023-09-30

The proEVLifeCycle network, initiated in Oct 2019, is an innovative, multidisciplinary training program focused on understanding the biology, biomarker potential and function of extracellular vesicles to resolve unmet clinical needs of prostate cancer (PCa). It is within this realm, that we equip early-stage researchers with the knowledge, tools and a creative ethos to be independent scientists, leaders, and drivers of innovation.

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 addresses 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 enlightens the lifecycle of EVs and identifies 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 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.
In order to integrate the various research efforts to uncover the role of EVs in PCa progression, the consortium aligned their (i) scientific protocols for EV isolation and quantification from different biofluids (urine, blood, saliva), (ii) PCa disease models (tumor cells and animal models), and (iii) identified all relevant public and consortium EV databases.

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) genetically manipulated 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 have successfully been used to identify sets of proteins in the cancer cells involved in making EVs and how EVs can travel through a layer of tightly packed cells that form a barrier. Utilizing mouse models, the role of integrins on the surface of EVs was linked to their biodistribution and PCa metastasis.

With respect to utilizing EVs from urine, blood and saliva as PCa biomarkers, the molecular characterization of EV (sub)populations focused on the content of EVs, which includes genetic material (RNA), proteins, and small molecules. Various candidate RNAs, proteins and their glycosylation status, as well as PCa-associated metabolites have been discovered. Novel detection assays have been developed and validation of the clinical added value of the candidate biomarkers is initiated.

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 clues how this would benefit the tumor cells to grow better and migrate to other organs to form metastases. This important information is design therapy interventions including the use of EVs as drug-carriers to bring chemo specifically to the tumor. Targeting of EVs and nanoparticles to PCa cells using nanobodies against the PCa protein PSMA, have shown efficacy in cultured PCa cells and in a zebrafish model system.

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 based on the integration of different datasets, identified new PCa-associated RNAs and pathway-regulators associated with neuro-endocrine and other PCa subtypes.
Besides the progress described above, new insights in the biology, biomarker potential and function of EVs, resulted in discovery of a number of novel therapeutic targets and treatment applications. Our 10 PhD students are finalizing their research and are on track to successfully graduate. They were exposed to the wide-range of aspects of science and ready to take on their next career step to further advance science and society.

The progress made within proEVLifeCycle is substantial and allows the next steps of independent validation and implementation. The socio-economic impact can 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, society and the medical health system.
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ProEVLifeCycle consortium at Fourth Network meeting in Cardiff