DEPARTMENT OF DEFENSE - CONGRESSIONALLY DIRECTED MEDICAL RESEARCH PROGRAMS

Investigating the Role of Fibroblasts in the Tumor Microenvironment and Hippo Signaling Pathway in Neurofibromas

Posted August 20, 2019

Lu Q. Le, M.D., Ph.D., University of Texas Southwestern Medical Center

  Lei Xu, M.D., Ph.D., Massachusetts General Hospital
Dr. Lu Q. Le,
University of Texas Southwestern Medical Center

Neurofibromatosis consists of a family of syndromes, including neurofibromatosis type I (NF1), neurofibromatosis type II (NF2), and schwannomatosis. These syndromes are caused by different genetic conditions that often cause tumors throughout the body, but are predominantly found in the nervous system. NF1 is one of the most common genetic disorders of the nervous system and is associated with mutations in the tumor suppressor gene, NF1, which encodes a negative regulator of the RAS signaling pathway. Complications from NF1 are diverse, affect multiple organ systems, and lead to the development of a wide array of growths, from benign cutaneous and plexiform neurofibromas to malignant peripheral nerve sheath tumors. Individuals with NF2 and schwannomatosis commonly develop complex schwannomas that lack specific, efficacious treatments to date and can infiltrate the nerves to cause chronic pain, numbness, and life-threatening neurological dysfunction.

With support from a Fiscal Year (FY) 2015 Exploration-Hypothesis Development Award through the Neurofibromatosis Research Program (NFRP), Dr. Lu Le and his team are investigating the contributions of fibroblasts in the pathogenesis of neurofibromas by defining the cellular interactions in the tumor microenvironment, specifically between neoplastic Schwann cells and fibroblasts. A recent publication [1] by the group describes an antagonistic role for NF1 heterozygosity in tumor initiation and malignant transformation, which they discovered through analysis of malignant and benign NF1-associated tumors and tumors with high frequency for NF1 gene mutation in the general population. Dr. Le and his team demonstrated that an Nf1+/- microenvironment accelerates benign tumor formation, but impairs further progression to malignancy in two independent mouse models representing NF1- and non-NF1-associated tumors.

Dr. Le was also awarded an FY16 Investigator-Initiated Research Award through the NFRP to define molecular and developmental pathogenesis of Schwann cell tumors and elucidate the mechanisms by which specific cancer pathways may affect tumor formation. The most recent publication [2] by Dr. Le and his group describes the role of HOXB7 as a lineage marker in mapping the origin of neoplastic cells within cutaneous neurofibroma (cNF), the most common tumor in NF1 patients. Through deletion of the Nf1 gene in HOXB7 lineage-derived cells, Dr. Le and his team successfully recapitulated cutaneous and plexiform human neurofibroma. Furthermore, this work demonstrated that neurofibroma tumorigenesis is susceptible to modification through modulation of the Hippo pathway, a signaling pathway that controls cell growth and has been implicated in numerous cancer types.

Through both NFRP awards, Dr. Le’s team has shed light on the role of the NF1 gene in both NF1 and non-NF1 patient contexts. If successful, Dr. Le’s work will pave the way toward understanding the developmental origin and biology of cNF. Furthermore, potential modifications to the Hippo pathway, in addition to NF1 deletion, may be an attractive therapeutic target for NF1 patients and could provide neurofibroma treatment options where none currently exist.

References:

  1. Brosseau JP, Liao CP, Wang Y, et al. 2018. NF1 heterozygosity fosters de novo tumorigenesis but impairs malignant transformation. Nature Communications 9(1):5014.
  1. Chen Z, Mo J, Brosseau JP, et al. 2019. Spatiotemporal loss of NF1 in Schwann cell lineage leads to different types of cutaneous neurofibroma susceptible to modification by the hippo pathway. Cancer Discovery 9(1):114.

Links:

Public and Technical Abstracts: Parallels between Nerve Scar Formation and Neurofibroma Development: The Contributions of Fibroblasts

Public and Technical Abstracts: Defining Molecular and Developmental Pathogenesis of Schwann Cell Tumors to Identify Therapeutic Targets

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Last updated Tuesday, August 20, 2019