EVs shuttle parent cell -derived molecules (proteins, lipids,metabolites and nucleic acids) from cells to other cells changing their phenotype and function, so our hypothesis is that they are extracellular organelles with a communicative function. Although currently the physiological role of EVs is understood to center on cell communication, EVs may also provide cells with a homeostatic way for self-regulation by e.g., disposing of unwanted material. The dynamic molecular reservoir of EVs presents a unique way for cells to participate in multicellular stepwise processes such as immune regulation, blood coagulation, wound healing, angiogenesis and tissue regeneration. In diseases from cardiovascular to cancer, EVs may analogously mediate mechanisms critical for pathogenesis. The EV group’s research focuses on better understanding the heterogeneity of platelet and cancer EVs including their subpopulations, functional properties and their applicability in diagnostics and therapy. The EV group also strives to develop and improve analytical methods and standardisation for EV research and further, to offer these to other researchers via the EV core.
EV group is affiliated to Molecular and Integrative Biosciences research programme (MIBS) and the Cancer Unit for Research for Expermental Drugs (CURED)
Platelets, as a blood component, participate in clotting and wound healing. Despite the well-established physiological contributions to the maintenance of tissue integrity, only a few roles have been described for platelets in pathological events in cancer development and progression, and the detailed underlying mechanisms have not been elucidated. Cancer patients experience platelet hyperactivity, and higher probability for the occurrence of venous thromboembolism. Once activated, platelets release their granule cargo and generate EVs, which also carry several bioactive molecules. In this context, platelet-derived EVs (PEVs) may also contribute to cancer progression and metastasis e.g., via releasing their content into the tumor microenvironment. Tumor cell interaction with platelets (also via tumor-derived EVs), known as platelet-tumor education, may support several hallmarks of cancer such as tumor growth, proliferation and survival. Therefore, our research group investigates the pathological contributions of PEVs to cancer cell behavior, especially melanoma, to better understand the molecular mechanisms associated with these processes. Reciprocally, we are interested in tumor-EV effects on platelet functions and signaling. These aims will be realised in the PLEASER project 2020-24, funded by the Academy of Finland.
EVs are released from all cell types including cancer cells and platelets and they carry both intravesicular and extravesicular cargo comprising e.g. mRNAs, miRNAs and other non-coding RNAs, proteins and metabolites which in the recipient cells may enable phenotypic or functional changes. By this rich cargo, EVs have a great potential to promote biomarker discovery. Our research group focuses on understanding how cancer milieu affects platelets and PEV cargo, and whether these changes can be detected from the plasma of patients. Our previous in vitro work showed that cancer EVs have molecular signatures that can be used for diagnostics in the future. Based on these results, we will look into the metabolomic fingerprint of cancer EVs in cutaneous T cell lymphoma (CTCL) and melanoma patients in collaboration with Professor Annamari Ranki's group.
Due to their barrier crossing properties and cellular uptake, EVs could also be utilized as drug delivery vehicles. EVs can be loaded with various therapeutic agents, including chemotherapeutic drugs and nucleic acids. Our previous work with prostate cancer cells showed that autologous cancer cell -derived EVs enhance the delivery of Paclitaxel into target cells and improved cell death. In our PLEASER project 2020-24, we will further explore the uptake potential of PEVs to evaluate their properties as drug delivery vehicles for melanoma and in the EVE project we will evaluate the the barrier-crossing properties of natural PEVs.
The "EV-ome" comprising the molecular content and subpopulations of EVs may have innate therapeutic potential, which could be potentially used in different applications in addition to natural or engineered EVs being used as vectors for drug delivery. Although stem cell -derived EVs have so far been in the spotlight, we believe that platelet EVs could provide a novel therapeutic source.
EVs are heterogeneous in their site of origin, size, surface properties and cargo, and the ratio of distinct populations may change depending on the stimulus their parent cells receive. To understand and harness the therapeutic potential of PEVs, our group is developing methods to induce, isolate, identify and characterize the effector subpopulations with the highest therapeutic activity and suitability for drug delivery. Our cell model, the platelet, is uniquely versatile in its signaling capacity and rich in therapeutically relevant cargo. We are developing methods to isolate specific PEV subpopulations to employ orthogonal single particle analyses and omics to characterize the profiles of these populations to learn more about their applicability in theranostics and the complexity underlying the EV-based cell communication.
This research is carried out in the BF-funded EVE project, and in the Academy of Finland- funded PLEASER and the post doctoral project of Mari Palviainen.
Due to the recent and extremely fast expansion of the EV field, the used isolation and characterization methods are variable, or they are non-existent e.g. separation of exosomes and microvesicles. Furthermore, misconceptions and methodological pitfalls hamper the progress in understanding the biological function of EVs. To improve the reliability and credibility of the reported findings, several methodological aspects needs to be addressed. There are three sources of variation that affect the outcome of EV measurements: 1) the sample itself (e.g. body fluid), 2) the pre-analytical phase (e.g. sample collection, handling, storage, EV isolation and purification), 3) the analytics (e.g. the hardware, and software used to detect EVs and analyze the obtained results). The scientific community increasingly recognizes the need to standardize methodology and technology, which has lead to launching many international standardization initiatives such as ISEV guidelines about the minimal information for studies of EVs (MISEV), EV-TRACK promoting transparent reporting and centralizing knowledge, and the EV Flow Cytometry Working Group initiated by ISAC (International Society for Advanced Sciences), ISEV and ISTH (International Society for Thrombosis). EV group has for long actively taken part in methodological development and standardization in the EV field e.g. MISEV and ISEV Rigor and Standardisation (Blood work group).
In 2019-2022 EV group participates in METVES II: Standardisation of concentration measurements of EVs for medical diagnoses, an EU –wide project, which aims to tap to the clinical potential of EVs by developing traceable measurements of number concentration, size distribution, refractive index and fluorescence intensity of cell-specific EVs in human blood and urine. In METVES II, EV group develops ready-to-use biological test samples from human urine, which will be evaluated in an inter-laboratory comparison study across a range of standard flow cytometers in clinical labs.
The EV group belongs to the Business Finland –funded consortium EVE –Extracellular Vesicle (EV) Ecosystem for Theranostic Platforms which brings together 13 Finnish academy and industry partners to drive the development of novel EV-based therapeutic and diagnostic solutions. In EVE, the EV group specifically addresses the therapeutic potential of platelet-derived EVs in close collaboration with the R&D of Finnish Red Cross Blood Service (FRCBS). For identification of the true clinical potential of EVs, the development of improved EV methodologies is a fundamental part of the EVE project. The EV group sets up, optimizes, and develops further several state-of-the-art technologies for EV assessment enabling orthogonal approaches, and develops protocols and guidelines for EV handling, storage, methodologies and analyses. The method development work is done in close collaboration with other EVE consortium partners such as FRCBS, VTT, and the groups of Tapani Viitala (UH) and Elina Vuorima-Laukkanen (TaU) and is further advanced through international collaboration with other EV initiatives in EU (e.g. METVES II), research organisations, and companies.
Also, issues relating to the small sample size and large number of samples, such as in cohort/biobank samples, need to be resolved. We address these issues as we progress within the individual research projects, but we also target these issues directly in the EV core where the EV group collaborates with Dr. Maija Puhka in the Finnish Institute of Molecular Medicine (FIMM).
EV group collaborates with many national and international researchers.
Dr. Saara Laitinen, Dr. Erja Kerkelä and Dr. Ulla Impola, Finnish Red Cross Blood Service
Dr. Annamari Ranki, University of Helsinki
Dr. Kirsi Rilla, University of Eastern Finland
Dr. Kati Öörni, Wihuri Research Institute
Dr. Tapani Viitala, University of Helsinki
Prof. Marjo Yliperttula, University of Helsinki
Dr. Rienk Nieuwland, The Amsterdam University Medical Centre, Netherlands
Prof. Juan Falcón-Pérez, CIC bioGUNE, Spain
COST action ME-HaD participants