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Tumor Biology

MON-329 - Tumorlet Formation and Abnormal Adrenal Medullary Development in SDHB-Deficient Mouse Model

Monday, June 15, 2026
9:00 AM - 2:00 PM CT
Location: ENDOExpo; Poster Floor

    Abstract Poster Presenter(s)

  • YC

    Yasemin C. Cole, PhD

    MD PhD Student
    Neuro-Oncology Branch, National Cancer Institute, National Institutes of Health
    Bethesda, Maryland, United States

    • Co-Author(s)

  • II

    Iris Indig, BA

    Neuro-Oncology Branch, National Cancer Institute, National Institutes of Health
    Bethesda, Maryland, United States

  • HW

    Herui Wang, PhD

    Staff Scientist
    National Cancer Institute, National Institutes of Health
    Bethesda, Maryland, United States

  • JR

    Jared Rosenblum, MD

    Neuro-Oncology Branch, National Cancer Institute, National Institutes of Health
    Long Branch, New Jersey, United States

  • SC

    Shuran Chen, BS

    Neuro-Oncology Branch, National Cancer Institute, National Institutes of Health
    Bethesda, Maryland, United States

  • LY

    LaYow Yu, BS

    Neuro-Oncology Branch, National Cancer Institute, National Institutes of Health
    Bethesda, Maryland, United States

  • JM

    Jeeva P. Munasinghe, PhD

    Staff Scientist
    Mouse Imaging Facility, National Institute of Neurological Disorders and Stroke, National Institutes of Health
    Bethesda, Maryland, United States

  • DD

    Danielle R. Donahue, n/a

    Mouse Imaging Facility, National Institute of Neurological Disorders and Stroke, National Institutes of Health
    Bethesda, Maryland, United States

  • AS

    Adam Sowalsky, PhD

    Laboratory of Genitourinary Cancer Pathogenesis, National Cancer Institute, National Institutes of Health
    Bethesda, Maryland, United States

  • ST

    Shana Trostel, BA

    Genitourinary Malignancies Branch, National Cancer Institute, National Institutes of Health
    Bethesda, Maryland, United States

  • HA

    Hussam Alkaissi, MD, MS

    NATIONAL INSTITUTES OF HEALTH (NIH)
    Bethesda, Maryland, United States

    • Senior Author/Primary Investigator(s)

  • Karel Pacak, MD,PhD,DSC, FACE (he/him/his)

    Director, Center for Adrenal Endocrine Tumors
    Akeso Holding and Masaryk University, Brno
    Prague 3, Czech Republic

    • Co-Author(s)

  • Karel Pacak, MD,PhD,DSC, FACE (he/him/his)

    Director, Center for Adrenal Endocrine Tumors
    Akeso Holding and Masaryk University, Brno
    Prague 3, Czech Republic

    • Senior Author/Primary Investigator(s)

  • ZZ

    Zhengping Zhuang, MD, PhD

    Neuro-Oncology Branch, National Cancer Institute, National Institutes of Health
    Bethesda, Maryland, United States

    • Co-Author(s)

  • ZZ

    Zhengping Zhuang, MD, PhD

    Neuro-Oncology Branch, National Cancer Institute, National Institutes of Health
    Bethesda, Maryland, United States

Advancing the care of patients with rare cancer syndromes is made possible by creating model systems to elucidate the mechanisms driving disease and by applying this knowledge to therapeutics. This is the case for patients with pheochromocytoma and paraganglioma (PPGL). PPGLs are rare, highly heritable neuroendocrine tumors derived from the neural crest (NC) that can present as early as the first decade of life. As a transitory group of migratory cells, the neural crest uniquely contributes to a diverse array of organs. When heterozygous hypomorphic genetic variants in genes encoding succinate dehydrogenase complex subunits (SDHx) are compounded by loss of heterozygosity (LOH), it leads to disruption of mitochondrial complex II and accumulation of succinate, resulting in inhibition of various dioxygenases, stabilization of hypoxia-inducible factors, genomic hypermethylation, vasculogenesis, and tumorigenesis. To better understand the implications of SDHB variants on NC and PPGL development, we evaluated a transgenic “two hit” SDHB mouse model developed to recapitulate the associated human PPGL syndrome using a multimodal approach of high-resolution ex vivo imaging, followed by immunohistochemistry (IHC) and ddPCR of adrenal glands. Adrenal medullae of Sdhb double hit mutants were significantly enlarged and displayed abnormal intra-adrenal features, including adrenal cortical nodules, medullary tails, and vascular defects, compared to Sdhb single hit adrenals. We observed enlarged, amphophilic, and vacuolated, clustered cells at the corticomedullary border in 72.7% (8/11) of mice, suggesting improper adrenal medullary development and tumorlet “Zellballen” formation. Despite a low variant allele frequency of ~1% in mutant adrenal medulla, adrenal glands contained significantly elevated succinate concentrations in line with SDHx deficient tumors. Taken together, these studies suggest that the Sdhb mutant allele is under selective pressure during early adrenal development, and that cells that escape this restriction form nested Zellballen structures, characteristic of PPGLs, and lead to an enlarged adrenal medulla. Both the timing of the acquired variant and the spatial localization of the defective cells demonstrate the critical nature of Sdhb in normal adrenal development.

*Unless otherwise noted, all abstracts presented at ENDO must not be released to the press or the public until the date and time of presentation. For oral presentations, the abstracts are embargoed until the session begins. The Endocrine Society reserves the right to lift the embargo on specific abstracts that are selected for promotion prior to or during ENDO.*