Abstract
Tuberous sclerosis complex (TSC) and Lymphangioleiomyomatosis (LAM) lack well-defined cellular origins, limiting treatment options. In this report, scRNA-seq of Tsc2+/− mouse renal cystadenomas revealed an 80-fold increase in a tumor cell subpopulation with neural crest features, and expressing known cranial neural crest genes as SRY box transcription factor 9 (Sox9), transcription factor activator protein (Tfap2a), and candidate neurocristopathy markers, osteopontin (Spp1), lipocalin-2 (Lcn2), clusterin (Clu), and cytokeratin 18 (Krt18). These signatures were validated in mouse tumors, and LAM patient lesions and serum, identifying a tumor phenotype distinct from traditional VEGFD detection. Pathway analysis indicated activation of WNT/SHH signaling, nephric duct formation, and pro-tumorigenic signals, with transcription factor 7 (Tcf7) and ephrin-A ligands as key upstream regulators. Spp1 KO in cranial neural crest cells (CNCCs) significantly reduced proliferation (28–33%), migration (54-76%), and invasion (29-64%) without affecting viability, while Tsc2 KO increased viability 3 to 6-fold with minimal impact on chemotaxis. Elevated serum levels of SPP1 and KRT18 in some LAM patients, decreased LCN2 in nearly all, and distinct increases in VEGFD suggest complementary roles for these biomarkers. Overall, findings support a neurocristopathic model of tumor development in TSC and LAM and identify potential biomarkers and therapeutic targets beyond mTOR inhibition.
Authors
Uchenna J. Unachukwu, Enio B. Garcia, Nooralam Rai, Jeanine M. D'Armiento
This file is in Adobe Acrobat (PDF) format. If you have not installed and configured the Adobe Acrobat Reader on your system.
Having trouble reading a PDF?
PDFs are designed to be printed out and read, but if you prefer to read them online, you may find it easier if you increase the view size to 125%.
Having trouble saving a PDF?
Many versions of the free Acrobat Reader do not allow Save. You must instead save the PDF from the JCI Online page you downloaded it from. PC users: Right-click on the Download link and choose the option that says something like "Save Link As...". Mac users should hold the mouse button down on the link to get these same options.
Having trouble printing a PDF?
- Try printing one page at a time or to a newer printer.
- Try saving the file to disk before printing rather than opening it "on the fly." This requires that you configure your browser to "Save" rather than "Launch Application" for the file type "application/pdf", and can usually be done in the "Helper Applications" options.
- Make sure you are using the latest version of Adobe's Acrobat Reader.
