CXCR4/CXCL12 mediate autocrine cell- cycle progression in NF1-associated malignant peripheral nerve sheath tumors

Wei Mo, Jian Chen, Amish Patel, Liang Zhang, Vincent Chau, Yanjiao Li, Woosung Cho, Kyun Lim, Jing Xu, Alexander J. Lazar, Chad J. Creighton, Svetlana Bolshakov, Renée M. McKay, Dina Lev, Lu Q. Le, Luis F. Parada

Research output: Contribution to journalArticlepeer-review

103 Scopus citations

Abstract

Malignant peripheral nerve sheath tumors (MPNSTs) are soft tissue sarcomas that arise in connective tissue surrounding peripheral nerves. They occur sporadically in a subset of patients with neurofibromatosis type 1 (NF1). MPNSTs are highly aggressive, therapeutically resistant, and typically fatal. Using comparative transcriptome analysis, we identified CXCR4, a G-protein-coupled receptor, as highly expressed in mouse models of NF1-deficient MPNSTs, but not in nontransformed precursor cells. The chemokine receptor CXCR4 and its ligand, CXCL12, promote MPNST growth by stimulating cyclin D1 expression and cell-cycle progression through PI3-kinase (PI3K) and β-catenin signaling. Suppression of CXCR4 activity either by shRNA or pharmacological inhibition decreases MPNST cell growth in culture and inhibits tumorigenesis in allografts and in spontaneous genetic mouse models of MPNST. We further demonstrate conservation of these activated molecular pathways in human MPNSTs. Our findings indicate a role for CXCR4 in NF1-associated MPNST development and identify a therapeutic target.

Original languageEnglish (US)
Pages (from-to)1077-1090
Number of pages14
JournalCell
Volume152
Issue number5
DOIs
StatePublished - Feb 28 2013

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)

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