Derivation of sarcomas from mesenchymal stem cells via inactivation of the Wnt pathway.
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/beta-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.
Matushansky
Igor
I
Department of Medicine, Columbia University, New York, New York 10032, USA. im17@columbia.edu
Hernando
Eva
E
Socci
Nicholas D
ND
Mills
Joslyn E
JE
Matos
Tulio A
TA
Edgar
Mark A
MA
Singer
Samuel
S
Maki
Robert G
RG
Cordon-Cardo
Carlos
C
D000818:Animals; D002454:Cell Differentiation / Q000502:physiology; D019070:Cell Lineage; D002471:Cell Transformation, Neoplastic; D020869:Gene Expression Profiling; D051677:Histiocytoma, Malignant Fibrous / Q000378:metabolism / Q000473:pathology; D006801:Humans; D036341:Intercellular Signaling Peptides and Proteins / Q000235:genetics / Q000378:metabolism; D048031:JNK Mitogen-Activated Protein Kinases / Q000378:metabolism; D059630:Mesenchymal Stem Cells / Q000166:cytology / Q000502:physiology*; D051379:Mice; D008819:Mice, Nude; D015398:Signal Transduction / Q000502:physiology*; D014407:Tumor Cells, Cultured; D051153:Wnt Proteins / Q000235:genetics / Q000378:metabolism*; D051176:beta Catenin / Q000378:metabolism
C501126:DKK1 protein, human; D036341:Intercellular Signaling Peptides and Proteins; D051153:Wnt Proteins; D051176:beta Catenin; D048031:JNK Mitogen-Activated Protein Kinases