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Intercellular Transfer of Splicing Factors via Extracellular Vesicles Promotes Glioblastoma Growth and Therapy Resistance
Author(s) -
Pavlyukov Marat S,
Mohyeldin Ahmed,
Shender Victoria O,
Minata Mutsuko,
Wang Jia,
Chen Dongquan,
Kim Sunghak,
Antipova Nadezhda V,
Shakhparonov Mikhail I,
Nakano Ichiro
Publication year - 2016
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.30.1_supplement.590.2
Subject(s) - microbiology and biotechnology , biology , microvesicles , intracellular , cancer cell , microrna , cancer , biochemistry , genetics , gene
Cell‐to‐cell communications are indispensable for any multicellular organism and the central nervous system probably relies on it more than any other organ. Emerging evidence indicates that extracellular vesicles (EVs) play pivotal roles in intercellular communications both in healthy and diseased brain. With the help of EVs, normal glial cells can protect neurons from damage and support their proper functions and development. Thus Schwann cells have recently been shown to transfer various cargoes such as proteins, RNAs, and even whole ribosomes to damaged axons in order to promote regeneration. Malignant glial cells also can enhance proliferation of neighboring tumor cells after different kinds of insults and thus contribute to tumor regeneration. This process was shown in various in vitro and in vivo models; however, the exact molecular mechanism remains unclear. The aim of this study was to elucidate molecular mechanisms of intercellular communication in glioblastoma tumors which are involved in tumor recurrence and treatment resistance. Our results indicate that EVs produced by apoptotic cells play an important role in tumor progression by enhancing proliferation, migration, and therapy resistance of glioblastoma cells. Comparison of EVs derived from “healthy” and apoptotic cancer cells by liquid chromatography–mass spectrometry and quantitative PCR revealed that EVs secreted by dying cells are greatly enriched with spliceosomal proteins and RNAs. Investigation of mechanisms underlying spliceosome export revealed that activation of caspases, which occurs after apoptosis induction, leads to cleavage of proteins responsible for anchorage of spliceosomes to chromatin. This cleavage causes dissociation of spliceosomes from nuclear matrix, its export to cytoplasm and further encapsulation into EVs. As expected, caspase inhibitors completely block this process. Most importantly, microarray data from apoptotic cells demonstrate expression of splicing factors, which are different from those in “healthy” tumor cells. Once exported into extracellular space, EVs that contain these “unusual” splicing factors can be taken up by neighboring cancer cells. Next splicing factors from EVs are transported to the nucleus of recipient cells and affect mRNA splicing. Ultimately, these changes in splicing program promote the expression of mesenchymal stem cell markers, which correlate with a more aggressive cellular phenotype and poor prognosis for patient survival. In summary, we show for the first time that spliceosomes can play an important role in intercellular communication of glioblastoma cells. These data may improve our understanding of mechanisms underlying tumor recurrence and therapy resistance, and on the other hand it might help to develop new, minimally invasive methods for cancer diagnostics based on detection of spliceosomal RNAs and proteins in blood of patients. Support or Funding Information This work was supported by the American Cancer Society MRSG‐08‐108‐01 and NIH/NCI P01 CA163205, R21 CA175875, NIH/NINDS R01 NS083767, R01 NS087913 and by the scholarship of the President of the Russian Federation