Single-cell functional analysis of parathyroid adenomas reveals distinct classes of calcium sensing behaviour in primary hyperparathyroidism.
Abstract
Primary hyperparathyroidism (PHPT) is a common endocrine neoplastic disorder caused
by a failure of calcium sensing secondary to tumour development in one or more of
the parathyroid glands. Parathyroid adenomas are comprised of distinct cellular subpopulations
of variable clonal status that exhibit differing degrees of calcium responsiveness.
To gain a clearer understanding of the relationship among cellular identity, tumour
composition and clinical biochemistry in PHPT, we developed a novel single cell platform
for quantitative evaluation of calcium sensing behaviour in freshly resected human
parathyroid tumour cells. Live-cell intracellular calcium flux was visualized through
Fluo-4-AM epifluorescence, followed by in situ immunofluorescence detection of the
calcium sensing receptor (CASR), a central component in the extracellular calcium
signalling pathway. The reactivity of individual parathyroid tumour cells to extracellular
calcium stimulus was highly variable, with discrete kinetic response patterns observed
both between and among parathyroid tumour samples. CASR abundance was not an obligate
determinant of calcium responsiveness. Calcium EC50 values from a series of parathyroid
adenomas revealed that the tumours segregated into two distinct categories. One group
manifested a mean EC50 of 2.40 mM (95% CI: 2.37-2.41), closely aligned to the established
normal range. The second group was less responsive to calcium stimulus, with a mean
EC50 of 3.61 mM (95% CI: 3.45-3.95). This binary distribution indicates the existence
of a previously unappreciated biochemical sub-classification of PHPT tumours, possibly
reflecting distinct etiological mechanisms. Recognition of quantitative differences
in calcium sensing could have important implications for the clinical management of
PHPT.
Type
Journal articleSubject
adenomacalcium
hyperparathyroidism
parathyroid
single-cell analysis
Adenoma
Calcium
Calcium Signaling
Cell Line
Humans
Hyperparathyroidism, Primary
Parathyroid Neoplasms
Receptors, Calcium-Sensing
Single-Cell Analysis
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https://hdl.handle.net/10161/12535Published Version (Please cite this version)
10.1111/jcmm.12732Publication Info
Koh, James; Hogue, Joyce A; Wang, Yuli; DiSalvo, Matthew; Allbritton, Nancy L; Shi,
Yuhong; ... Sosa, Julie A (2016). Single-cell functional analysis of parathyroid adenomas reveals distinct classes of
calcium sensing behaviour in primary hyperparathyroidism. J Cell Mol Med, 20(2). pp. 351-359. 10.1111/jcmm.12732. Retrieved from https://hdl.handle.net/10161/12535.This is constructed from limited available data and may be imprecise. To cite this
article, please review & use the official citation provided by the journal.
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Show full item recordScholars@Duke
James Koh
Assistant Professor of Surgery
The major effort in the lab is directed towards investigating how tumor-specific dysregulation
of the pRB signaling pathway affects downstream gene expression and the cellular response
to DNA damage. Four projects are currently underway. First, we are utilizing a modified
chromatin immunoprecipitation approach to capture and identify genomic DNA target
sequences conditionally associated with pRB-containing complexes recovered from intact
chromatin in untransformed primary human cells. Se
Julie Ann Sosa
Professor of Surgery
Julie Ann Sosa, MD MA FACS is Chief of Endocrine Surgery at Duke University and leader
of the endocrine neoplasia diseases group in the Duke Cancer Institute and the Duke
Clinical Research Institute. She is Professor of Surgery and Medicine. Her clinical
interest is in endocrine surgery, with a focus in thyroid cancer. She is widely published
in outcomes analysis, as well as cost-effectiveness analysis, meta-analysis, and survey-based
research, and she is director of health services research for
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