Funded Research
February 15, 2009: The Liddy Shriver Sarcoma Initiative is funding a 1-year $50,000 research study, "Tumorigenic Cells in Malignant Peripheral Nerve Sheath Tumors," to Sean J. Morrison, PhD at the Life Sciences Institute in the Center for Stem Cell Biology at the University of Michigan in Ann Arbor, Michigan. The funding of this grant is made possible, in part, by the generous donations made by the family and friends in loving memory of James Stulce who lost his life to this disease.
The following appears in the abstract of Professor Morrison’s grant application:
About 10% of patients with neurofibromatosis develop malignant peripheral nerve sheath tumors (MPNSTs), very aggressive and invasive soft tissue sarcomas, which are often refractory to chemotherapy and radiotherapy. This project’s first objective (Specific Aim 1) is to determine if the progression of MPNSTs follows a cancer stem cell model, in which only a small minority of cancer cells is capable of extensive proliferation or if many MPNST cells are able to sustain tumor growth. To test this, we will use mouse models for MPNSTs bearing mutations in Nf1, Ink4Arf and p53. If we find that only a subset of cells drive tumor formation, we will attempt to isolate those MPNST-initiating (tumorigenic) cells so that we can study the regulation of self-renewal in these cells.
The project’s second objective (Specific Aim 2) is to identify molecular mechanisms that allow tumorigenic cells to self-renew. Cancer cells often inappropriately activate signaling pathways that regulate the self-renewal of normal stem cells. We have shown that plexiform neurofibromas and MPNSTs arise from non-myelinating Schwann cells that under normal physiological conditions remain quiescent in peripheral nerves (Cancer Cell 13:129). To test if cancer cells arising from differentiated glia reactivate stem cell self-renewal mechanisms, we will compare the gene expression profiles of tumorigenic cells isolated from primary MPNSTs, mature non-myelinating Schwann cells from normal adult peripheral nerves, glial restricted progenitors from fetal nerves, and multipotent neural crest stem cells from fetal nerves. Comparing these cell populations will allow us to test whether the gene expression profiles of adult MPNST cells undergo changes that re-activate pathways that are employed by fetal glial progenitors or by stem cells, but which are not active in adult Schwann cells. This may lead to the identification of new therapeutic targets. One potential new target that we have already identified is the high mobility group transcription factor Hmga2, which is highly expressed in neural crest stem cells and human MPNST cells and which we have recently discovered to regulate the self-renewal of neural crest stem cells (Cell 135:227).
Our third objective (Specific Aim 3) is to test whether Hmga2 is required for the formation or growth of MPNSTs. By generating compound mutant mice, we will test if the loss of Hmga2 affects the formation or growth of MPNSTs that arise in Nf1/Ink4a/Arf or Nf1/p53 mutant mice. Preliminary results suggest that a high percentage of cells isolated from MPNSTs is able to transfer disease when transplanted into syngeneic mice, suggesting that these cancers do not follow a cancer stem cell model in contrast to many other cancers. This could help to explain why these cancers are so aggressive and refractory to therapy. Our experiments will provide new insights into the molecular and cellular mechanisms that regulate the growth and progression of MPNSTs.
You can read more about this study in the article, "Do many, or few, cells within malignant peripheral nerve sheath tumors have the potential to contribute to disease progression?" which appears in the February 2009 issue of ESUN.
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