Derivation of sarcomas from mesenchymal stem cells via inactivation of the Wnt pathway

Igor Matushansky, Eva Hernando, Nicholas D. Socci, Joslyn E. Mills, Tulio A. Matos, Mark A. Edgar, Samuel Singer, Robert G. Maki, Carlos Cordon-Cardo

Research output: Contribution to journalArticlepeer-review

154 Scopus citations

Abstract

Malignant fibrous histiocytoma (MFH), now termed high-grade undifferentiated pleomorphic sarcoma, is a commonly diagnosed mesenchymal tumor, yet both the underlying molecular mechanisms of tumorigenesis and cell of origin remain unidentified. We present evidence demonstrating that human mesenchymal stem cells (hMSCs) are the progenitors of MFH. DKK1, a Wnt inhibitor and mediator of hMSC proliferation, is overexpressed in MFH. Using recombinant proteins, antibody depletion, and siRNA knockdown strategies of specific Wnt elements, we show that DKK1 inhibits hMSC commitment to differentiation via Wnt2/β-catenin canonical signaling and that Wnt5a/JNK noncanonical signaling regulates a viability checkpoint independent of Dkk1. Finally, we illustrate that hMSCs can be transformed via inhibition of Wnt signaling to form MFH-like tumors in nude mice, and conversely, MFH cells in which Wnt signaling is appropriately reestablished can differentiate along mature connective tissue lineages. Our results provide mechanistic insights regarding the cell of origin of MFH, establish what we believe is a novel tumor suppressor role for Wnt signaling, and identify a potential therapeutic differentiation strategy for sarcomas.

Original languageEnglish
Pages (from-to)3248-3257
Number of pages10
JournalJournal of Clinical Investigation
Volume117
Issue number11
DOIs
StatePublished - 1 Nov 2007
Externally publishedYes

Fingerprint

Dive into the research topics of 'Derivation of sarcomas from mesenchymal stem cells via inactivation of the Wnt pathway'. Together they form a unique fingerprint.

Cite this