Single‐Cell Transcriptomic Atlas of Parathyroid Adenoma and Parathyroid Carcinoma

Abstract

Primary hyperparathyroidism is typically characterized by monoclonal parathyroid tumors that secrete an excessive amount of parathyroid hormone (PTH). However, the underlying pathogenesis of tumorigenesis remains unclear. We performed single‐cell transcriptomic analysis on five parathyroid adenoma (PA) and two parathyroid carcinoma (PC) samples. A total of 63,909 cells were divided into 11 different cell categories; endocrine cells accounted for the largest proportion of cells in both PA and PC, and patients with PC had larger populations of endocrine cells. Our results revealed significant heterogeneity in PA and PC. We identified cell cycle regulators that may play a critical role in the tumorigenesis of PC. Furthermore, we found that the tumor microenvironment in PC was immunosuppressive, and endothelial cells had the highest interactions with other cell types, such as fibroblast‐musculature cells and endocrine cells. PC development may be stimulated by fibroblast‐endothelial cell interactions. Our study clarifies the transcriptional signatures that underlie parathyroid tumors and offer a potential significant contribution in the study of pathogenesis of PC. © 2023 American Society for Bone and Mineral Research (ASBMR).

Fibroblast-based FN1CFD contributes to parathyroid cancer identification using integrated analysis

“…We have reported that iCAF marker genes including CFD, CXCL12, and IGF1 were enriched in PA samples and mCAF marker genes were highly expressed in PC samples. However, it was reported that the iCAF were mainly observed enriched in PC samples in one sc-RNAseq data incorporating 2 PA and 5 PA samples [19]. This opposite conclusion might result from the small cohort data, indicating the role of iCAF in parathyroid tumors needs further investigation.…”

“…To comprehensively clarify the role of CAF, we manually collected signature genes of iCAF and mCAF [18]. The following genes were seen as markers of parathyroid parenchyma cells: PTH, CHGA, RARRES2, PVALB, CISD1, CASR, GCM2, KLCASR, VDR, LRP2, EPCAM, SLC17A5 [19][20][21]. The collected genes were rearranged and can be found in TableS2.…”

KMT2A and chronic inflammation as potential drivers of sporadic parathyroid adenoma

“…76,77 However, whether it is involved in PA pathogenesis remains unclear, although the infiltration of immune cells into the PA microenvironment has been well documented. 28,78 Our analysis of stromal cells revealed that the PA microenvironment is markedly more proinflammatory than that of PG tissues. First, PA fibroblasts displayed primarily a phenotype similar to inflammatory cancer-associated fibroblasts 57,58 ; second, ECs in the PA microenvironment were strongly activated, expressing a range of genes necessary for immune cell extravasation; third, the frequency of myeloid cells was markedly higher in PA relative to PT tissues, and the inflammatory_response pathway was upregulated in PA macrophages; fourth, the angiogenesis pathway was enriched in T and NK cells from PAs compared with those from PGs, indicative of the inflammatory response, 79,80 although numerous hallmark gene signature pathways were downregulated, and last, PACs and PA fibroblasts, in contrast to PGCs and PG fibroblasts, received TNF signalling.…”

“…What are the mechanisms of the dysregulation of gene expression in PA stromal cells? Moreover, given the highly heterogeneous nature of PAs, 28,78…”

“…What are the mechanisms of the dysregulation of gene expression in PA stromal cells? Moreover, given the highly heterogeneous nature of PAs, 28 , 78 the relatively small number of PA cases included in this study leaves open the question of how representative the identified mechanisms are. Investigation in larger clinical cohorts is clearly desirable to further validate our findings.…”