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Neural Crest Cell Signatures Drive TSC and LAM Tumorigenesis

ABSTRACT: This study was performed to test the hypothesis that neural crest cells (NCCs) are causative cells for multi-systemic neoplasms occurring in Tuberous Sclerosis Complex (TSC) and Lymphangioleiomyomatosis (LAM) disorders. The hypothesis stemmed from the mesenchymal phenotypes of TSC and LAM neoplasms and their occurrence in patients at known ontogenetic destinations for maturing neural crest cells. We determined differential gene expression between single cell populations in wildtype mice renal cortical tissues versus renal cystadenomas of the tuberous sclerosis mice model by RNA sequencing, and validated our findings by immunohistochemistry, RT-qPCR, western blots, and tumorigenicity assays. Based on our results, we pioneer the characterization of cranial NCC-induced tumorigenesis in TSC and LAM and identify the crucial role of novel neurocristopathic markers: secreted phosphoprotein (SPP1) and cytokeratin 18 (Krt18) in disease pathogenesis. Genetic inhibition of Spp1 yields an anti-tumorigenic phenotypes in NCCs.

ORGANISM(S): Mus musculus

PROVIDER: GSE291150 | GEO | 2026/03/03

REPOSITORIES: GEO

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Neural Crest Cell Signatures Drive TSC and LAM Tumorigenesis [human]

Project description:This study was performed to test the hypothesis that neural crest cells (NCCs) are causative cells for multi-systemic neoplasms occurring in Tuberous Sclerosis Complex (TSC) and Lymphangioleiomyomatosis (LAM) disorders. The hypothesis stemmed from the mesenchymal phenotypes of TSC and LAM neoplasms and their occurrence in patients at known ontogenetic destinations for maturing neural crest cells. We determined differential gene expression between single cell populations in wildtype mice renal cortical tissues versus renal cystadenomas of the tuberous sclerosis mice model by RNA sequencing, and validated our findings by immunohistochemistry, RT-qPCR, western blots, and tumorigenicity assays. Based on our results, we pioneer the characterization of cranial NCC-induced tumorigenesis in TSC and LAM and identify the crucial role of novel neurocristopathic markers: secreted phosphoprotein (SPP1) and cytokeratin 18 (Krt18) in disease pathogenesis. Genetic inhibition of Spp1 yields an anti-tumorigenic phenotypes in NCCs.

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Integrative Single Cell Multiomic Profiling Analysis Reveals HOX-PBX Gene Regulatory Network Regulating the Survival of mTOR Hyperactive Cells [snRNA-Seq]

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Modulation of infiltrating CD206-positive macrophages restricts progression of pulmonary lymphangioleiomyomatosis (LAM)

Project description:Lymphangioleiomyomatosis (LAM) is a very rare disease affecting women of childbearing age, either sporadically or in association with tuberous sclerosis complex (TSC). The proliferation of TSC2 null LAM cells in the lung results in cystic destruction, airflow obstruction, respiratory insufficiency and eventually death. In the LAM lung, the tumor immune microenvironment (TME) plays a role in the progression of LAM lesions. Macrophages can be polarized into inflammatory M1 macrophages or protumorigenic immunosuppressive M2 macrophages. Macrophages are an important component of the TME, and we hypothesized that CD206+ M2 macrophages could facilitate LAM progression and represent a potential therapeutic target.

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Transcriptomic profiling of Neural Progenitors Cell and Neural Crest Cell Differentiation of Wild-Type and TSC2-Knockout Cultures from the Pluripotent State

Project description:TSC2 inactivating mutations elicit mTORC1 hyperactivation and underlie neurological dysfunction and the development of neural and mesenchymal tumors in the monogenic disease tuberous sclerosis complex (TSC). We present a multi-lineage model of TSC2-deficiency employing CRISPR-Cas9 engineering in human pluripotent stem cells (hPSCs) and differentiation into neural and neural crest lineages, cell types predicted to drive TSC manifestations. Temporal RNA-sequencing reveals a massive proteostatic stress response underlying early neuroepithelial induction of TSC2-deficient cells, which is resolved upon neural crest cell (NCC) specification but persists in neural precursor cells (NPCs). This culminates in long-term endosomal and metabolic reprogramming as cells age, and sensitivity of TSC2-/- NPCs, but not NCCs, to death via proteasome inhibition independent of mTORC1 activity. Thus, TSC2-deficiency induces lineage-specific stress adaptations which confer differential sensitivity to a commonly targeted pathway. These results exemplify the complexity of elucidating underlying biological mechanisms and therapeutic approaches for multisystem diseases, illustrating the power of utilizing hPSC disease models with tissue-specific relevance.

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Expression data from Tsc2-null cell line ELT3, and the ELT3-derivative rapamycin-resistant cell line ELT3-245

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