title: The neural crest lineage as a driver of disease heterogeneity in Tuberous Sclerosis Complex and Lymphangioleiomyomatosis.
abstract: Lymphangioleiomyomatosis (LAM) is a rare neoplastic disease, best characterized by the formation of proliferative nodules that express smooth muscle and melanocytic antigens within the lung parenchyma, leading to progressive destruction of lung tissue and function. The pathological basis of LAM is associated with Tuberous Sclerosis Complex (TSC), a multi-system disorder marked by low-grade tumors in the brain, kidneys, heart, eyes, lung and skin, arising from inherited or spontaneous germ-line mutations in either of the TSC1 or TSC2 genes. LAM can develop either in a patient with TSC (TSC-LAM) or spontaneously (S-LAM), and it is clear that the majority of LAM lesions of both forms are characterized by an inactivating mutation in either TSC1 or TSC2, as in TSC. Despite this genetic commonality, there is considerable heterogeneity in the tumor spectrum of TSC and LAM patients, the basis for which is currently unknown. There is extensive clinical evidence to suggest that the cell of origin for LAM, as well as many of the TSC-associated tumors, is a neural crest cell, a highly migratory cell type with extensive multi-lineage potential. Here we explore the hypothesis that the types of tumors that develop and the tissues that are affected in TSC and LAM are dictated by the developmental timing of TSC gene mutations, which determines the identities of the affected cell types and the size of downstream populations that acquire a mutation. We further discuss the evidence to support a neural crest origin for LAM and TSC tumors, and propose approaches for generating humanized models of TSC and LAM that will allow cell of origin theories to be experimentally tested. Identifying the cell of origin and developing appropriate humanized models is necessary to truly understand LAM and TSC pathology and to establish effective and long-lasting therapeutic approaches for these patients.
authors.affiliation: Sprott Centre for Stem Cell Research, Regenerative Medicine Program, Ottawa Hospital Research Institute Ottawa, ON, Canada ; Faculty of Graduate and Postdoctoral Studies, University of Ottawa Ottawa, ON, Canada ; Department of Cellular and Molecular Medicine, University of Ottawa Ottawa, ON, Canada.
authors.forename: Sean P
authors.initials: SP
authors.lastname: Delaney
authors.affiliation: Sprott Centre for Stem Cell Research, Regenerative Medicine Program, Ottawa Hospital Research Institute Ottawa, ON, Canada ; Faculty of Graduate and Postdoctoral Studies, University of Ottawa Ottawa, ON, Canada.
authors.forename: Lisa M
authors.initials: LM
authors.lastname: Julian
authors.affiliation: Sprott Centre for Stem Cell Research, Regenerative Medicine Program, Ottawa Hospital Research Institute Ottawa, ON, Canada ; Faculty of Graduate and Postdoctoral Studies, University of Ottawa Ottawa, ON, Canada ; Department of Cellular and Molecular Medicine, University of Ottawa Ottawa, ON, Canada ; Department of Biochemistry, Microbiology, and Immunology, University of Ottawa Ottawa, ON, Canada.
authors.forename: William L
authors.initials: WL
authors.lastname: Stanford
keywords: Lymphangioleiomyomatosis; Tuberous Sclerosis; cell of origin; disease modeling; neural crest