FUS-CHOP Fusion Protein Expression Coupled to p53 Deficiency Induces Liposarcoma in Mouse but Not in Human Adipose-Derived Mesenchymal Stem/Stromal Cells

Abstract

Human sarcomas have been modeled in mice by expression of specific fusion genes in mesenchymal stem cells (MSCs). However, sarcoma models based on human MSCs are still missing. We attempted to develop a model of liposarcoma by expressing FUS (FUsed in Sarcoma; also termed TLS, Translocated in LipoSarcoma)-CHOP (C/ EBP HOmologous Protein; also termed DDIT3, DNA Damage-Inducible Transcript 3), a hallmark mixoid liposarcoma-associated fusion oncogene, in wild-type and p53-deficient mouse and human adipose-derived mesenchymal stem/stromal cells (ASCs). FUS-CHOP induced liposarcoma-like tumors when expressed in p53 2/2 but not in wild-type (wt) mouse ASCs (mASCs). In the absence of FUS-CHOP, p53 2/2 mASCs forms leiomyosarcoma, indicating that the expression of FUS-CHOP redirects the tumor genesis/phenotype. FUS-CHOP expression in wt mASCs does not initiate sarcomagenesis, indicating that p53 deficiency is required to induce FUS-CHOP-mediated liposarcoma in fat-derived mASCs. In a human setting, p53-deficient human ASCs (hASCs) displayed a higher in vitro growth rate and a more extended lifespan than wt hASCs. However, FUS-CHOP expression did not induce further changes in culture homeostasis nor initiated liposarcoma in either wt or p53-depleted hASCs. These results indicate that FUS-CHOP expression in a p53-deficient background is sufficient to initiate liposarcoma in mouse but not in hASCs, suggesting the need of additional cooperating mutations in hASCs. A microarray gene expression profiling has shed light into the potential deregulated pathways in liposarcoma formation from p53-deficient mASCs expressing FUS-CHOP, which might also function as potential cooperating mutations in the transformation process from hASCs. STEM CELLS 2011; 29:179-192 Disclosure of potential conflicts of interest is found at the end of this article.

Modeling sarcomagenesis using multipotent mesenchymal stem cells

“…Nevertheless, in contrast to BM-mMSCs, secondary cooperating hits such as p53 deficiency are required for liposarcoma development from mASCs, suggesting that BM-mMSCs are more susceptible to FUS-CHOP-induced transformation and sarcomagenesis than mASCs. In the absence of FUS-CHOP, p53 −/− mASCs originated leiomyosarcoma [31], indicating that the expression of FUS-CHOP redirects the tumor genesis/phenotype [40]. These studies support the contention that the FUS-CHOP fusion is a critical event in MLS pathogenesis and that MSCs may represent the liposarcoma-initiating cell.…”

“…For instance, opposite to mMSCs the inactivation of p53 or p53 and Rb does not induce transformation in hMSCs, although p53-/Rb-deficient hMSCs display a higher growth rate in vitro coupled to an extended lifespan [39,40]. In order to efficiently induce in vivo sarcomas from hMSCs, several non-physiological oncogenic events had to be combined [41,42] (Table 2).…”

“…Thus, mice carrying a homozygous deletion of PTEN (a negative regulator of the PI3K-AKT pathway) in the smooth muscle lineage efficiently developed leiomyosarcoma [46]. The involvement of PTEN and PI3K-AKT in leiomyosarcoma is also implicated by the fact that these signaling pathways are dysregulated in leiomyosarcoma-forming p53-decifient mMSCs [40].…”

“…More importantly, the expression of FUS-CHOP in both BM-mMSCs and mASCs gave rise to MLS-like tumors [40,65]. Nevertheless, in contrast to BM-mMSCs, secondary cooperating hits such as p53 deficiency are required for liposarcoma development from mASCs, suggesting that BM-mMSCs are more susceptible to FUS-CHOP-induced transformation and sarcomagenesis than mASCs.…”

“…In the human setting, EWS-FLI-1-expressing hMSCs failed to originate tumors when injected into immunodeficient mice, [59] npg expression, which could be involved in liposarcoma development, including PDGF signaling, RXR signaling, and sphingolipid and fatty acid metabolism [40,65].…”