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@ARTICLE{Sun:144733,
      author       = {H. Sun and S. Rana and Z. Wang and K. Zhao and M.
                      Schnölzer$^*$ and J. Provaznik and T. Hackert and Q. Lv and
                      M. Zöller},
      title        = {{T}he {P}ancreatic {C}ancer-{I}nitiating {C}ell {M}arker
                      {CD}44v6 {A}ffects {T}ranscription, {T}ranslation, and
                      {S}ignaling: {C}onsequences for {E}xosome {C}omposition and
                      {D}elivery.},
      journal      = {Journal of oncology},
      volume       = {2019},
      issn         = {1687-8469},
      address      = {New York, NY},
      publisher    = {Hindawi Publ. Corp.},
      reportid     = {DKFZ-2019-02165},
      pages        = {3516973},
      year         = {2019},
      abstract     = {Pancreatic cancer-initiating cells (PaCIC) express CD44v6
                      and Tspan8. A knockdown (kd) of these markers hinders the
                      metastatic capacity, which can be rescued, if the cells are
                      exposed to CIC-exosomes (TEX). Additional evidence that
                      CD44v6 regulates Tspan8 expression prompted us to explore
                      the impact of these PaCIC markers on nonmetastatic PaCa and
                      PaCIC-TEX. We performed proteome, miRNA, and mRNA deep
                      sequencing analyses on wild-type, CD44v6kd, and Tspan8kd
                      human PaCIC and TEX. Database comparative analyses were
                      controlled by qRT-PCR, Western blot, flow cytometry, and
                      confocal microscopy. Transcriptome analysis of CD44 versus
                      CD44v6 coimmunoprecipitating proteins in cells and TEX
                      revealed that Tspan8, several signal-transducing molecules
                      including RTK, EMT-related transcription factors, and
                      proteins engaged in mRNA processing selectively associate
                      with CD44v6 and that the membrane-attached CD44
                      intracytoplasmic tail supports Tspan8 and NOTCH
                      transcription. Deep sequencing uncovered a CD44v6
                      contribution to miRNA processing. Due to the association of
                      CD44v6 with Tspan8 in internalization prone
                      tetraspanin-enriched membrane domains (TEM) and the
                      engagement of Tspan8 in exosome biogenesis, most
                      CD44v6-dependent changes were transferred into TEX such that
                      the input of CD44v6 to TEX activities becomes largely waved
                      in both a CD44v6kd and a Tspan8kd. Few differences between
                      CD44v6kd- and Tspan8kd-TEX rely on CD44v6 being also
                      recovered in non-TEM derived TEX, highlighting distinct TEX
                      delivery from individual cells that jointly account for
                      TEX-promoted target modulation. This leads us to propose a
                      model in which CD44v6 strongly supports tumor progression by
                      cooperating with signaling molecules, altering transcription
                      of key molecules, and through its association with the mRNA
                      processing machinery. The association of CD44v6 with Tspan8,
                      which plays a crucial role in vesicle biogenesis, promotes
                      metastases by transferring CD44v6 activities into TEM and
                      TEM-independently derived TEX. Further investigations of the
                      lead position of CD44v6 in shifting metastasis-promoting
                      activities into CIC-TEX may offer a means of targeting
                      TEX-CD44v6 in therapeutic applications.},
      cin          = {B100},
      ddc          = {610},
      cid          = {I:(DE-He78)B100-20160331},
      pnm          = {312 - Functional and structural genomics (POF3-312)},
      pid          = {G:(DE-HGF)POF3-312},
      typ          = {PUB:(DE-HGF)16},
      pubmed       = {pmid:31485223},
      pmc          = {pmc:PMC6702834},
      doi          = {10.1155/2019/3516973},
      url          = {https://inrepo02.dkfz.de/record/144733},
}