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Researchers identify cell-of-origin for plexiform neurofibroma tumours.

UT Southwestern Medical Center researchers have determined the specific type of cell that gives rise to large, disfiguring tumours called plexiform neurofibromas, a finding that could lead to new therapies for preventing growth of these tumours.  The opensource study is published in the journal Cancer Cell.

This advance provides new insight into the steps that lead to tumour development and suggests ways to develop therapies to prevent neurofibroma formation where none exist today.

Plexiform neurofibromas, which are complex tumours that form around nerves, occur in patients with a genetic disorder called neurofibromatosis type 1 (NF1), which affects 1 in 3,500 people. About 30 percent of NF1 patients develop this type of tumour, which is typically benign.

NF1 patients with plexiform neurofibromas, however, have a 10 percent lifetime risk of the tumours developing into malignant peripheral nerve sheath tumours (MPNSTs), a deadly, incurable type of soft-tissue cancer. In addition, due to their unusual capacity for growth, plexiform neurofibromas can be life-threatening by their physical impairment of vital organs or neural function.

While there are no currently approved therapies for either MPNSTs or plexiform neurofibromas, the team state that determining the cell type and location from which these tumours originate is an important step toward discovering new drugs that inhibit tumour development.

If researchers can isolate and grow the cells of origin for neurofibromas, then they can reconstruct the biological steps that lead these original cells to tumour stage.  Once the medical community know the critical steps in the process, then they can design inhibitors to block each step in an effort to prevent or slow tumour formation.

Using a process called genetic labelling for cell fate tracing, researchers determined that plexiform neurofibromas originate from Schwann cell precursors in embryonic nerve roots.

This study addresses a fundamental question in the neurofibromatosis field.  It points to the importance of stem cells and their immediate progenitors in the initiation of tumours, consistent with the notion that these neoplasms originate in a subset of primitive precursors and that most cells in an organ do not generate tumours.

In a related study published last year, the team found that inhibiting the action of a protein called BRD4 caused tumours to shrink in a mouse model of MPNST.

The team state that new drugs are desperately needed to treat both MPNST and plexiform neurofibromas and are now working with a pharmaceutical company to bring a BRD4-inhibiting drug into clinical trials for MPNST patients.

Source:  UT Southwestern Medical Center

Neurofibromatosis type 1 is a tumor-predisposing genetic disorder. Plexiform neurofibromas are common NF1 tumors carrying a risk of malignant transformation, which is typically fatal. Little is known about mechanisms mediating initiation and identity of specific cell type that gives rise to neurofibromas. Using cell-lineage tracing, we identify a population of GAP43+ PLP+ precursors in embryonic nerve roots as the cells of origin for these tumors and report a non-germline neurofibroma model for preclinical drug screening to identify effective therapies. The identity of the tumor cell of origin and facility for isolation and expansion provides fertile ground for continued analysis to define factors critical for neurofibromagenesis. It also provides unique approaches to develop therapies to prevent neurofibroma formation in NF1 patients.  Cells of Origin in the Embryonic Nerve Roots for NF1-Associated Plexiform Neurofibroma.  Chen et al 2014.
Neurofibromatosis type 1 is a tumor-predisposing genetic disorder. Plexiform neurofibromas are common NF1 tumors carrying a risk of malignant transformation, which is typically fatal. Little is known about mechanisms mediating initiation and identity of specific cell type that gives rise to neurofibromas. Using cell-lineage tracing, we identify a population of GAP43+ PLP+ precursors in embryonic nerve roots as the cells of origin for these tumors and report a non-germline neurofibroma model for preclinical drug screening to identify effective therapies. The identity of the tumor cell of origin and facility for isolation and expansion provides fertile ground for continued analysis to define factors critical for neurofibromagenesis. It also provides unique approaches to develop therapies to prevent neurofibroma formation in NF1 patients. Cells of Origin in the Embryonic Nerve Roots for NF1-Associated Plexiform Neurofibroma. Chen et al 2014.

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