Leiomyosarcoma Research Study Funded

The Liddy Shriver Sarcoma Initiative and Leiomyosarcoma Direct Research Foundation (a.k.a., LMSdr and LMSarcoma Direct Research Foundation) are pleased to announce the joint funding of a research project to be undertaken by Eva Hernando, PhD of the Experimental Pathology Program in the Department of Pathology and her team at the NYU School of Medicine. The $50,000 year long grant, which is titled, "MicroRNA Deregulation in Mesenchymal Transformation and Sarcoma-genesis" will begin shortly, The specific sarcoma under investigation is leiomyosarcoma.

MicroRNAs (miRNAs) are endogenous small RNAs that interfere with the translation of coding messenger RNAs (mRNAs) in a sequence specific manner, playing a critical role in the regulation of gene expression during development and tissue homeostasis. Certain miRNAs have been shown to tightly modulate the expression of oncogenes (e.g. MYC and RAS) or tumor suppressors, and have been found deregulated in different tumor types. Recently, miRNAs have been revealed as useful tools for the molecular classification of tumors. However, to date, miRNA expression has not been analyzed in sarcomas. This project represents the first attempt to classify leiomyosarcomas based on their miRNA profile, and to explore the contribution of miRNAs to the smooth-muscle oncogenic transformation process.

It is usually believed that sarcomas derive from mature mesenchymal cells. Thus, the transformation of chondrocytes would originate a chondrosarcoma, adipocytes would be the cell of origin of liposarcomas, and smooth-muscle cells of leiomyosarcoma. However, many sarcomas of a certain subtype vary in their differentiation features. For instance, liposarcomas can be subclassified in de-differentiated, myxoid, pleomorphic, well-differentiated, depending on how close they resemble adypocitic features. Even different areas in the same tumor can contain more or less mature cells. Therefore, our view of the sarcoma "cell of origin" has changed. Instead of a mature cell that "de-differentiates" during the neoplastic process, it is now believed that a mesenchymal progenitor becomes a tumor cell before it is fully mature. According to this model, the leiomyosarcoma cell of origin could be a myoblast rather than a smooth muscle cell.

Recently a new type of small RNAs has been identified that do not codify for proteins, but control the expression of other RNAs that do encode proteins (messenger RNAs or mRNAs). This new group of small RNAs, called microRNAs, have the ability to repress or silence many genes during critical processes, such as development. It is being shown that certain microRNAs can control gene expression during mesenchymal differentiation. Dr. Hernando and her team hypothesize that specific microRNAs can regulate the maturation of functional smooth muscle cells from myoblasts and that alterations in these miRNAs can contribute to the transformation of these myoblasts into tumor cells, contributing to sarcoma-genesis.

Evidence for a contribution of miRNA deregulation to the oncogenic process has been obtained in other tumor types. For instance, let-7 has been found down-regulated in lung cancer. Let-7 usually represses the oncogene RAS; thus, low levels of let-7 will lead to RAS-mediated transformation. Moreover, different tumor types are characterized by a specific set of altered miRNAs. More importantly, these "miRNA expression signatures" seem able to predict outcome. For instance, let-7 downregulation correlates with poor prognosis in lung cancer patients. Overall, these data strongly indicate that miRNAs play an important role in human cancer.

Dr. Hernando and her tem have received human mesenchymal stem cells from Tulane University and cultured them in vitro following the recommendations of Dr. Prockop’s laboratory. They are able to differentiate human mesenchymal stem cells into smooth muscle cells, confirmed by the expression of markers and contraction under appropriate stimuli. First, they will analyze the microRNA expression profile of mesenchymal stem cells differentiating into smooth muscle cells and define a ‘smooth muscle miRNA differentiation signature’: a subset of microRNAs whose expression changes during the normal smooth muscle differentiation process. Then, they will compare these with the miRNAs expressed by leiomyosarcomas, in order to identify miRNAs abnormally expressed in LMS compared to normal smooth muscle progenitors. Moreover, they will attempt to identify miRNAs whose expression associates with different clinical/pathological parameters, particularly with patient survival. These miRNAs could be used as prognostic markers, which will be confirmed in an independent set of tumors.

In the future, Dr. Hernando and her team will test the ability of candidate microRNAs to transform smooth muscle progenitors. They will also identify the target genes of the microRNAs of interest, as potentially directly responsible for sarcoma-genesis. It is hoped that this research will lead to: 1) a more accurate patient classification and the identification of prognostic biomarkers; 2) a better understanding of the pathogenesis of leiomyosarcoma; and, 3) unraveling potential new targets for future therapeutic intervention. Finally, their experimental approach should also offer a solid basis for similar studies in other sarcoma subtypes.

Click here to read the NYU Press Release announcing this grant.

V4N3 ESUN Copyright © 2007 Liddy Shriver Sarcoma Initiative.