TY  - JOUR
A1  - Leikam, C
A1  - Hufnagel, AL
A1  - Otto, C
A1  - Murphy, DJ
A1  - Mühling, B
A1  - Kneitz, S
A1  - Nanda, I
A1  - Schmid, M
A1  - Wagner, TU
A1  - Haferkamp, S
A1  - Bröcker, E-B
A1  - Schartl, M
A1  - Meierjohann, S
T1  - In vitro evidence for senescent multinucleated melanocytes as a source for tumor-initiating cells
JF  - Cell Death and Disease
N2  - Oncogenic signaling in melanocytes results in oncogene-induced senescence (OIS), a stable cell-cycle arrest frequently characterized by a bi-or multinuclear phenotype that is considered as a barrier to cancer progression. However, the long-sustained conviction that senescence is a truly irreversible process has recently been challenged. Still, it is not known whether cells driven into OIS can progress to cancer and thereby pose a potential threat. Here, we show that prolonged expression of the melanoma oncogene N-RAS\(^{61K}\) in pigment cells overcomes OIS by triggering the emergence of tumor-initiating mononucleated stem-like cells from senescent cells. This progeny is dedifferentiated, highly proliferative, anoikis-resistant and induces fast growing, metastatic tumors. Our data describe that differentiated cells, which are driven into senescence by an oncogene, use this senescence state as trigger for tumor transformation, giving rise to highly aggressive tumor-initiating cells. These observations provide the first experimental in vitro evidence for the evasion of OIS on the cellular level and ensuing transformation.
KW  - reactive oxygen
KW  - human melanoma
KW  - MITF
KW  - cancer
KW  - skin
KW  - DNA damage
KW  - kappa-B
KW  - oncogene-induced senescence
KW  - cellular senescence
Y1  - 2015
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-148718
VL  - 6
IS  - e1711
ER  - 
TY  - JOUR
A1  - Schatton, Tobias
A1  - Yang, Jun
A1  - Kleffel, Sonja
A1  - Uehara, Mayuko
A1  - Barthel, Steven R.
A1  - Schlapbach, Christoph
A1  - Zhan, Qian
A1  - Dudeney, Stephen
A1  - Mueller, Hansgeorg
A1  - Lee, Nayoung
A1  - de Vries, Juliane C.
A1  - Meier, Barbara
A1  - Beken, Seppe Vander
A1  - Kluth, Mark A.
A1  - Ganss, Christoph
A1  - Sharpe, Arlene H.
A1  - Waaga-Gasser, Ana Maria
A1  - Sayegh, Mohamed H.
A1  - Abdi, Reza
A1  - Scharffetter-Kochanek, Karin
A1  - Murphy, George F.
A1  - Kupper, Thomas S.
A1  - Frank, Natasha Y.
A1  - Frank, Markus H.
T1  - ABCB5 Identifies Immunoregulatory Dermal Cells
JF  - Cell Reports
N2  - Cell-based strategies represent a new frontier in the treatment of immune-mediated disorders. However, the paucity of markers for isolation of molecularly defined immunomodulatory cell populations poses a barrier to this field. Here, we show that ATP-binding cassette member B5 (ABCB5) identifies dermal immunoregulatory cells (DIRCs) capable of exerting therapeutic immunoregulatory functions through engagement of programmed cell death 1 (PD-1). Purified Abcb5\(^+\) DIRCs suppressed T cell proliferation, evaded immune rejection, homed to recipient immune tissues, and induced Tregs in vivo. In fully major-histocompatibility-complex-mismatched cardiac allotransplantation models, allogeneic DIRCs significantly prolonged allograft survival. Blockade of DIRC-expressed PD-1 reversed the inhibitory effects of DIRCs on T cell activation, inhibited DIRC-dependent Treg induction, and attenuated DIRC-induced prolongation of cardiac allograft survival, indicating that DIRC immunoregulatory function is mediated, at least in part, through PD-1. Our results identify ABCB5\(^+\) DIRCs as a distinct immunoregulatory cell population and suggest promising roles of this expandable cell subset in cellular immunotherapy.
KW  - mesenchymal stem cells
KW  - P-glycoprotein
KW  - regulatory T cells
KW  - maintain immune homeostasis
KW  - malignant melanoma
KW  - in vivo
KW  - skin
KW  - generation
KW  - transplant
KW  - tolerance
Y1  - 2015
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-149989
VL  - 12
SP  - 1564
EP  - 1574
ER  -