Different sarcomas of a certain histological subtype, or even different areas in the same tumor, display various levels of maturation. This observation has changed the traditional view of the "sarcoma cell-of-origin"- a mature cell that "de-differentiates" during the neoplastic process- for a mesenchymal progenitor in which differentiation is partially blocked or retains self-renewal and multipotent capacity. A limitation for these studies is our partial understanding of the normal differentiation process of mesenchymal cells. Professor Hernando has recently reported a leiomyosarcoma mouse model based on the inactivation of Pten in early smooth-muscle progenitors (using the Tgln promoter). Using this mouse model, the derived mesenchymal stem cells and human sarcomas, this lab plans to identify the leiomyo-sarcoma "cell of origin", isolate and characterize potential "cancer stem cells", and investigate the relationship between these two entities. Results from these studies might apply to other tumors on which, unlike leukemias or other classic developmental tumors, a crosstalk between cell differentiation and neoplastic transformation has not been explored in depth.
Matushansky I, Hernando E, Socci ND, Matos T, Mills J, Edgar MA, Singer S, Cordon-Cardo C, Maki RG. A developmental model of sarcomagenesis defines a differentiation-based classification for liposarcomas. Am J Pathol. 172(4):1069-80. (2008)
Hernando E; Charytonowicz E; Dudas ME; Menendez S; Matushansky I; Mills J; Socci ND; Behrendt N; Ma L; Maki RG; Pandolfi PP; Cordon-Cardo C. "The AKT-mTOR pathway plays a critical role in the development of leiomyosarcomas". Nature Medicine. 2007; 13: 748
Matushansky I., Hernando E., Edgar M.E., Singer, S., Schwartz, G.K., Maki R.G. Cordon-Cardo C. Derivation of sarcomas from mesenchymal stem cells via inactivation of the Wnt pathway. J Clin Invest. 117(11):3248-3257 (2007).