Discovery of the new mechanism of signaling complex transfer from cancer cells with extracellular vesicles

Extracellular vesicle-mediated transfer of constitutively active MyD88L265P engages MyD88wt and activates the recipient cells shaping cancer microenvironment.

Cells react to environmental changes by transmitting the signals, which induce processes like inflammatory response. MyD88 protein is important in immune response signaling induced by infection or other injuries. On the other hand, exaggerated cell activation can lead to pathologies. In Waldenström’s macroglobulinaemia (WM), a type of B-cell lymphoma, MyD88L265P mutation has been observed in >90% of patients. MyD88L265P triggers receptor independent cell activation. Blocking of MyD88 signaling induces cancer cell death and researchers from the National Institute of Chemistry previously reported on molecular mechanism of activation in 2014 https://www.ki.si/en/news/single-prikaz/achievement/novica/odkritje-molekulskega-mehanizma-razvoja-limfoma/.

Researchers from the Department of Synthetic Biology and Immunology from the National Institute of Chemistry discovered that extracellular vesicles released from cancer cells contain MyD88L265P. This mediator of signaling was transferred through vesicles to the neighboring cells and triggered their activation, which might contribute to the cancer development.

The first author of the research dr. Mateja Manček Keber has been researching the role of extracellular vesicles (EVs) for several years. EVs are submicron membrane-delimited vesicles which encapsulate cytosolic proteins, oligosaccharides, lipids and RNAs. EVs are released from cells and are present in all biological fluids. The physiological role of EVs lies in their capacity to transmit the information from the donor to recipient cells, which has been shown to be parcticularly important for cancer.

Researchers showed that MyD88L265P was transferred via EVs into the cytoplasm of the recipient cells, recruiting the endogenous MyD88 that triggered activation of the proinflammatory signaling. Additionally, internalization of EVs containing MyD88L265P was observed in mice along with the effect on the bone marrow microenvironment. MyD88-loaded EVs were also detected in the bone marrow aspirates of WM patients, demonstrating that this process is relevant in cancer patients. Results established the mechanism of transmission of signaling complexes via EVs to propagate inflammation as a new mechanism of intercellular communication, which might aupport a novel strategy in cancer therapy.

Results were published in the leading journal in the field of hematology Blood with an impact factor of 13.1 (http://www.bloodjournal.org/content/early/2018/01/19/blood-2017-09-805499?sso-checked=true).

Authors of the research are Mateja Manček Keber, Duško Lainšček, Mojca Benčina from National Institute of Chemistry, Rok Romih from Institute of Cell Biology, Faculty of Medicine, University of Ljubljana, Jiaji G. Chen, Zachary R. Hunter and Steven P. Treon from Dana Farber Cancer Institute, Harvard Medical School from Boston, USA, probably the most respectable center for the therapy of this type of cancer and Roman Jerala from the National Institute of Chemistry that lead the research.

 



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