The Le Laboratory is composed of a core group of talented research scientists, postdoctoral fellows, students and research associates. Our work bridges the fields of Cancer Biology, Developmental Biology, and Stem Cell Biology that focuses on neural-crest derived tissue development, regeneration, and tumorigenesis, in particular, the biology of neurofibromatosis, a group of genetic disorders that causes tumors to form on nerve tissue.
Our broad research goals are to 1) decipher mechanisms that initiate and drive human cancer, 2) generate robust in vivo and in vitro models to delineate tumor progression and 3) develop novel therapeutic targets for human cancers. A related goal is to translate our basic scientific discoveries in the laboratory into human clinical trials. Our primary scientific interests include identifying the cell of origin of tumorigenesis and elucidating the roles of tumor microenvironment in cancer development. Our laboratory dissects these cellular and molecular mechanisms of tumorigenesis from the developmental perspective. We utilize Neurofibromatosis Type 1, a common tumor predisposition human genetic disorder, as a model to address these two fundamental questions in Cancer Biology as well as elucidating cutaneous nervous system development and regeneration.
A major contribution of our laboratory is the generation and exploitation of novel neurofibromatosis models to elucidate mechanisms that initiate neurofibroma, a Schwann cell tumor, development and drive their malignant transformation. Our work has identified the cells of origin for different types of neurofibroma [Cancer Cell 26(5): 695-706; Cell Stem Cell 4(5):453-63], defined developmental “window-of-opportunity” within Schwann cell lineage for neurofibroma development [Cancer Research 71(13):4686-95]; and delineated vital cancer pathways for its malignant transformation into Malignant Peripheral Nerve Sheath Tumors, which account for 10% of all soft tissue sarcomas, and are lethal cancers whose pathways of activation are poorly understood. [Cell, 152(5): 1077-1090; Cell Reports, 6(1): 81-92; Cancer Research, 74(2): 586-97]. These and current studies in our laboratory address fundamental, unanswered questions in the neurofibromatosis field. They will not only provide important insights into the molecular and cellular pathogenesis of neurofibromatosis but also could lead directly to novel and potentially effective therapies aimed at delaying or preventing tumor formation in neurofibromatosis patients, where no curative treatment exists today.
Clinically, the neurofibromatosis program at UT Southwestern Medical Center is the primary neurofibromatosis clinic to provide specialized, comprehensive medical care for neurofibromatosis patients in North Texas and surrounding areas. Dr. Le serves as the co-director and attending physician of this clinic. This neurofibromatosis clinic also provides a platform for development and implementation of clinical trials, patient registry and tissue bank with the goal of developing more effective guidelines for neurofibromatosis clinical care as well as advancement of scientific research in the neurofibromatosis field.
In addition, it was this work in neurofibromatosis and mechanisms whereby neural-crest derived tissues and nerves can affect tumor development in skin and other tissues that serendipitously lead us to uncover the identity of follicular epithelial cells that directly give rise to hair and mechanisms that cause hair to turn gray [Genes & Development. 31(8): 744-756] – findings that could one day help identify possible treatments for balding and hair graying.
Neurofibromatosis
Neurofibromatosis encompasses a group of three complex neuro-cutaneous genetic disorders that causes tumors to form on nerve tissues and other manifestations. They arise from changes in different genes that lead to different clinical presentations. The three distinctive types of neurofibromatosis are:
Cutaneous neurofibromas covering the back of an individual with NF1 
Plexiform neurofibroma on an individual with NF1 
Immunofluorescence staining of a plexiform neurofibroma. Cover of JID, August 2023. 
Video: Surgical removal of cutaneous neurofibroma von Recklinghausen's Neurofibromatosis Type 1 (NF1) is one of the most common human genetic disorders, affecting 1 in 3,000 live births. NF1 occurs worldwide independent of sex, race, or geographic location. It is caused by mutations in the NF1 tumor suppressor gene, which encodes a GTPase activating protein (GAP) that negatively regulates p21-RAS signaling. Key features of NF1, which typically appear during childhood, are café au lait macules, axillary and groin freckling, and multiple peripheral nerve tumors called neurofibromas. Dermal or cutaneous neurofibromas (cNF) are strictly confined to the skin and do not progress to malignant lesions. cNFs are present in virtually all NF1 patients and can be as numerous as thousands of tumors that cover most of the body surface. Neurofibromas involving the internal nerve plexus are called plexiform neurofibromas (pNF). They are located below the dermis and have an increased risk of malignancy: 8 - 13% of pNFs undergo malignant transformation into malignant peripheral nerve sheath tumors (MPNSTs), which are lethal. Neurofibromas are complex tumors composed mainly of abnormal local cells including Schwann cells, nerves, endothelial cells, fibroblasts, and a large number of infiltrating immune cells. Recent work has demonstrated a critical role for the tumor microenvironment in neurofibroma genesis.
Currently, there is no curative treatment for NF1, with surgical removal being the main treatment. Unfortunately, surgery presents a challenge for many patients, some of whom may have thousands of these tumors. Also, surgical procedures are inaccessible to many NF1 patients globally. Therefore, a better understanding of the molecular mechanisms underlying neurofibroma development, as well as the interaction of the tumor cells with the cells in the microenvironment will provide a foothold to develop new therapies aimed at delaying or preventing tumor formation in NF1 patients.
The Le Lab is investigating how early, initiating genetic events such as loss of NF1 interplay with microenvironmental factors to regulate tumorigenesis. While great strides have been made, major knowledge gaps remain in the field including: 1) What drives the oncogenic progression of pNF to MPNST? 2) What is the role of the tumor microenvironment in neurofibromagenesis, and which cell types are involved? 3) Other knowledge gaps in the field pertain to the NF1 gene itself. How does loss of NF1 initiate neurofibroma formation and are certain NF1 mutations associated with certain clinical presentation? These are just a few questions among many regarding NF1 that remain to be answered.
Researchers and clinicians around the world have made important contributions to the NF field, and continue to work to address the knowledge gaps discussed above. A main focus of the lab is to identify the developmental origin or the cell(s) of origin that give rise to NF – a major knowledge gap in the field. The Le Lab developed novel NF models to address this question, including a 3-D in vitro cell culture system, and xenograft and genetically engineered mouse models that recapitulate human neurofibromas. [J Clin Invest, 131(1):e139807; Cancer Cell, 26(5):695-706; Cancer Discovery, 9(1):114-129; Stem Cells, 30(10):2261-2270; Cell Stem Cell, 4(5):453-463]. Using these models, the team was able to identify the cells of origin for pNF and cNF. These studies have also provided important insights into the molecular and cellular pathogenesis of NF and have served as a foothold for development of novel therapies for preventing or delaying tumor formation in NF patients [J Clin Invest, 131(1):e139807; Clin Cancer Res, 25(11):3404-3416; J Clin Invest, 128(7):2848-2861; Nat Communications, 9:5014; Cell Reports, 6(1):81-92; Cell, 152(5):1077-1090; Cancer Research,74(2):586-597; Cancer Research, 71(13):4686-4695].
Video: Surgical removal of cNF
While research is underway to find an effective medical treatment for cNF, which is the greatest burden for individuals with NF1, there is an urgent need to develop a surgical approach that is accessible to most NF1 patients in the world. Dr. Le has developed a robust surgical method to remove cNF that does not require a sterile surgical field, utilizes accessible clinical equipment, and can be performed by any health care provider including family practitioners and physician assistants [JCI Insight, 4(11)e128881;1-9]. Other management strategies for cNF are discussed here: Neuro-Oncology Adv, 2(S1):i107-i116.
For more information, visit the Texas Neurofibromatosis Foundation, Neurofibromatosis Network, Neurofibromatosis Midwest, and Children’s Tumor Foundation.
Clinical Manifestations of NF1 
Like Neurofibromatosis Type 1 (NF1), Neurofibromatosis Type 2 (NF2) is characterized by the development of slow-growing tumors in the nervous system, particularly along the nerves in the ears. These bilateral “acoustic” or ”vestibular” schwannomas are hallmarks of NF2 and can lead to deafness. Tumors can also grow along other nerves in the body including cranial, spinal, optic, and peripheral nerves. Individuals with NF2 can also develop cataracts and meningioma. Thus, other symptoms may include numbness, pain, vision loss, and balance issues. While these tumors are typically benign, they do have the potential to become malignant. NF2 is much less frequent in the population than NF1, affecting 1 in 25,000, and symptoms appear later, during the teen or early adult years.
The NF2 tumor suppressor gene encodes a cytoskeletal protein called Merlin. Merlin regulates cell signaling pathways that are involved in cell proliferation, growth, invasion, and adhesion. Similar to NF1, there is no cure for NF2. Treatment for NF2 typically involves monitoring and surgery if necessary, with chemotherapy and radiation therapy recommended in some situations.
Using genetically engineered mouse models, the Le Lab has provided direct genetic evidence that dysregulation of the Hippo signaling pathway, which is downstream of Merlin (NF2), can mediate schwannomagenesis, and that RAS/MAPK signaling can modify schwannoma development [JCI Insight, 5(20)141514]. These studies provide important insights into the molecular mechanisms underlying schwannomagenesis and offer promising targets for therapeutic strategies.
For more information, visit the Texas Neurofibromatosis Foundation, Neurofibromatosis Network, Neurofibromatosis Midwest, and Children’s Tumor Foundation.
Clinical Manifestations of NF2 
Schwannomatosis patient with a schwannoma growing on their neck 
Schwannomatosis is a recently characterized third major form of neurofibromatosis that lacks the hallmark bilateral acoustic (vestibular) schwannomas of NF2. Of the three types of neurofibromatosis, schwannomatosis is the least common, affecting less than 1 in 40,000. Schwannomas are benign tumors of Schwann cell origin, and patients with schwannomatosis develop multiple schwannomas throughout the body. These schwannomas can compress nearby nervous tissue and cause significant neurological impairment resulting in pain, numbness, and weakness of the extremities. The pain can be particularly debilitating and is often the first presenting symptom. Even after surgical removal of the tumor, the pain can still remain, indicating there are factors inherent to the nerves as the pain can occur in areas that do not have schwannoma. This is a major knowledge and clinical gap: why is there still pain and how can this pain be managed? Furthermore, schwannomas can undergo rare malignant transformation and cause life-threatening invasion of nearby vital organs. In schwannomatosis, schwannomas typically develop in adulthood. Management of the condition is based on each individual's symptoms. Surgery can be performed to remove the schwannoma, although sometimes surgery is not possible due to the location of the tumor. In addition to NF2, several newly identified genes including LZTR1 and SMARCB1, have been implicated in schwannoma development in Schwannomatosis, however their molecular roles are poorly defined.
Using genetically engineered mouse models, the Le Lab has found that dysregulation of the Hippo pathway can mediate schwannoma formation, and that RAS/MAPK signaling can modify schwannoma development [JCI Insight, 5(20)141514]. These studies provide important insights into the molecular mechanisms underlying schwannoma development and offer promising targets for therapeutic strategies.
For more information, visit the Texas Neurofibromatosis Foundation, Neurofibromatosis Network, Neurofibromatosis Midwest, and Children’s Tumor Foundation.
Clinical Manifestations of Schwannomatosis (those in red are most common)