My long-term career objective is to become a highly productive, independent translational investigator active in experimental therapeutics designed to translate state-of-the-art research in cellular differentiation and tissue regeneration into effective new differentiation-based therapies for human malignancies. My more immediate research objective is to study the relationship between tumorigenesis and differentiation using sarcomas and mesenchymal stem cells (MSCs) as a model system. I have found that DKK1, a Wnt inhibitor, has a powerful role in inhibiting commitment of MSCs to mesenchymal differentiation and promoting sarcomagenesis. Here, I propose to build on my preliminary data to define the role of DKK1 and its mechanism of action in sarcomagenesis by: a) examining the dependence of MSC-derived sarcomas on DKK1 for maintaining the tumorigenic phenotype;b) assessing the role of DKK1 in promoting MSC proliferation and sarcomagenesis in vivo by carefully characterizing undifferentiated/hyperproliferated mesenchymal tissue formed in developing mice (that I have recently generated) expressing DKK1 under a mesenchymal specific promoter;and c) assessing the mechanism by which DKK1 is deregulated in MSCs leading to their sarcomagenesis by examining whether or not DKK1 is transcriptionally regulated by the recently identified undifferentiated sarcoma specific oncogene - JUN;a transcription factor with known binding sites in the DKK1 promoter. I believe that this work will not only establish a novel tumor promoting function of DKK1 in MSCs but also identify its central role in sarcomagenesis. This work is designed to lead to the exploration of specific novel targeted therapies for sarcoma;a cancer that has historically proven to be unresponsive to established treatments. This project will also allow me to further develop my expertise in mouse modeling, mesenchymal stem cell biology, transcriptional regulation and sarcomagenesis thus generating essential expertise in the relationship between MSC differentiation and sarcomagenesis. During this training award I will be primarily mentored by Dr. Carlos Cordon-Cardo, an expert in mouse cancer modeling. Additionally, a multi-disciplinary team consisting of Dr. Jeremy Mao (an expert on MSC-tissue engineering), Dr. Gerard Karsenty (an expert on Wnt/musculoskeletal development), and Dr. Edward Gelmann (an expert on Wnt/(-catenin and transcriptional regulation) will provide further guidance and assistance as part of my mentoring/guidance committee. This research will take place at Columbia University Medical Center and the Herbert Irving Comprehensive Cancer Center.
|Zhang, X; Cruz, F D; Terry, M et al. (2013) Terminal differentiation and loss of tumorigenicity of human cancers via pluripotency-based reprogramming. Oncogene 32:2249-60, 2260.e1-21|
|Dela Cruz, Filemon; Terry, Melissa; Matushansky, Igor (2012) A transgenic, mesodermal specific, Dkk1 mouse model recapitulates a spectrum of human congenital limb reduction defects. Differentiation 83:220-30|
|Mills, Joslyn; Hricik, Todd; Siddiqi, Sara et al. (2011) Chromatin structure predicts epigenetic therapy responsiveness in sarcoma. Mol Cancer Ther 10:313-24|
|Siddiqi, Sara; Mills, Joslyn; Matushansky, Igor (2010) Epigenetic remodeling of chromatin architecture: exploring tumor differentiation therapies in mesenchymal stem cells and sarcomas. Curr Stem Cell Res Ther 5:63-73|
|Mills, Joslyn; Matos, Tulio; Charytonowicz, Elizabeth et al. (2009) Characterization and comparison of the properties of sarcoma cell lines in vitro and in vivo. Hum Cell 22:85-93|
|Matushansky, Igor; Charytonowicz, Elizabeth; Mills, Joslyn et al. (2009) MFH classification: differentiating undifferentiated pleomorphic sarcoma in the 21st Century. Expert Rev Anticancer Ther 9:1135-44|