PMID- 28165469
OWN - NLM
STAT- MEDLINE
DCOM- 20170727
LR  - 20230216
IS  - 1530-0307 (Electronic)
IS  - 0023-6837 (Print)
IS  - 0023-6837 (Linking)
VI  - 97
IP  - 6
DP  - 2017 Jun
TI  - Notch3 signaling-mediated melanoma-endothelial crosstalk regulates melanoma 
      stem-like cell homeostasis and niche morphogenesis.
PG  - 725-736
LID - 10.1038/labinvest.2017.1 [doi]
AB  - Melanoma is among the most virulent cancers, owing to its propensity to 
      metastasize and its resistance to current therapies. The treatment failure is 
      largely attributed to tumor heterogeneity, particularly subpopulations possessing 
      stem cell-like properties, ie, melanoma stem-like cells (MSLCs). Evidence 
      indicates that the MSLC phenotype is malleable and may be acquired by non-MSLCs 
      through phenotypic switching upon appropriate stimuli, the so-called 'dynamic 
      stemness'. Since the phenotypic characteristics and functional integrity of MSLCs 
      depend on their vascular niche, using a two-dimensional (2D) melanoma-endothelium 
      co-culture model, where the MSLC niche is recapitulated in vitro, we identified 
      Notch3 signaling pathway as a micro-environmental cue governing MSLC phenotypic 
      plasticity via pathway-specific gene expression arrays. Accordingly, lentiviral 
      shRNA-mediated Notch3 knockdown (KD) in melanoma cell lines exhibiting high 
      levels of endogenous Notch3 led to retarded/abolished tumorigenicity in vivo 
      through both depleting MSLC fractions, evinced by MSLC marker downregulation (eg, 
      CD133 and CD271); and impeding the MSLC niche, corroborated by the attenuated 
      tumor angiogenesis as well as vasculogenic mimicry. In contrast, Notch3 KD 
      affected neither tumor growth nor MSLC subsets in a melanoma cell line with 
      relatively low endogenous Notch3 expression. Thus, Notch3 signaling may 
      facilitate MSLC plasticity and niche morphogenesis in a cell context-dependent 
      manner. Our findings illustrate Notch3 as a molecular switch driving melanoma 
      heterogeneity, and provide the biological rationale for Notch inhibition as a 
      promising therapeutic option.
FAU - Hsu, Mei-Yu
AU  - Hsu MY
AD  - Department of Dermatology, Boston University Medical Center, Boston, MA, USA.
FAU - Yang, Moon Hee
AU  - Yang MH
AD  - Department of Dermatology, Boston University Medical Center, Boston, MA, USA.
FAU - Schnegg, Caroline I
AU  - Schnegg CI
AD  - Department of Dermatology, Boston University Medical Center, Boston, MA, USA.
FAU - Hwang, Soonyean
AU  - Hwang S
AD  - Department of Dermatology, Boston University Medical Center, Boston, MA, USA.
FAU - Ryu, Byungwoo
AU  - Ryu B
AD  - Department of Dermatology, Boston University Medical Center, Boston, MA, USA.
FAU - Alani, Rhoda M
AU  - Alani RM
AD  - Department of Dermatology, Boston University Medical Center, Boston, MA, USA.
LA  - eng
GR  - R01 CA138649/CA/NCI NIH HHS/United States
PT  - Journal Article
PT  - Research Support, N.I.H., Extramural
PT  - Research Support, Non-U.S. Gov't
DEP - 20170206
PL  - United States
TA  - Lab Invest
JT  - Laboratory investigation; a journal of technical methods and pathology
JID - 0376617
RN  - 0 (Receptor, Notch3)
SB  - IM
MH  - Animals
MH  - Cell Line, Tumor
MH  - Coculture Techniques
MH  - Human Umbilical Vein Endothelial Cells
MH  - Humans
MH  - Melanoma/*metabolism
MH  - Mice
MH  - Neoplastic Stem Cells/*metabolism
MH  - Receptor, Notch3/*metabolism
MH  - Signal Transduction
MH  - Stem Cell Niche/*physiology
MH  - Tumor Microenvironment/*physiology
PMC - PMC5446297
MID - NIHMS838887
COIS- Disclosure/Duality of Interest: No potential conflicts of interest were 
      disclosed.
EDAT- 2017/02/07 06:00
MHDA- 2017/07/28 06:00
PMCR- 2017/08/06
CRDT- 2017/02/07 06:00
PHST- 2016/06/03 00:00 [received]
PHST- 2016/11/25 00:00 [revised]
PHST- 2016/12/22 00:00 [accepted]
PHST- 2017/02/07 06:00 [pubmed]
PHST- 2017/07/28 06:00 [medline]
PHST- 2017/02/07 06:00 [entrez]
PHST- 2017/08/06 00:00 [pmc-release]
AID - S0023-6837(22)01238-7 [pii]
AID - 10.1038/labinvest.2017.1 [doi]
PST - ppublish
SO  - Lab Invest. 2017 Jun;97(6):725-736. doi: 10.1038/labinvest.2017.1. Epub 2017 Feb 
      6.