SFEBES2023 Oral Communications Endocrine Cancer and Late Effects (6 abstracts)
Cellular landscape of adrenocortical carcinomas at single-nuclei resolution
David Tourigny 1 , Barbara Altieri 2 , Kerim Secener 3 , Silviu Sbiera 2 , Marc Schauer 2 , Panagiota Arampatzi 4 , Sascha Sauer 5 , Martin Fassnacht 2 & Cristina Ronchi 1
1University of Birmingham, Birmingham, United Kingdom. 2University Hospital of Wuerzburg, Wuerzburg, Germany. 3Max Delbrück Center for Molecular Medicine, Berlin, Germany. 4University of Wuerzburg, Wuerzburg, Germany. 53Max Delbrück Center for Molecular Medicine, Berlin, Germany
BackgroundAdrenocortical carcinoma (ACC) is a rare but devastating tumour of the adrenal gland and the molecular mechanisms of pathogenesis remain incompletely understood. To gain novel insights into the cellular landscape of ACC, we compared single nuclei RNA sequencing (snRNA-seq) datasets from ACC and normal adrenal glands (NAGs).
Methods: We isolated single nuclei from 12 ACC snap-frozen samples, including 6 primary tumours, 3 local recurrent adrenal tumours and 3 metastatic lesions from 8 different patients. snRNA-Seq was performed using inDropTM technology. Data analysis, integration and exploration was performed using the Seurat R package. Initial cell types were predicted using NAG as a reference, combined with unsupervised clustering followed by differential gene expression and hallmark gene set analysis.
Results: We found the ACC tumour microenvironment to be relatively devoid of immune cells compared to NAG tissues, consistent with known high tumour purity values for ACC as an immunologically cold tumour. Our analysis revealed 7 subpopulations of ACC-specific adrenocortical cell types, including two populations of mitotically active cells strongly overexpressing MKI67 and DIAPH3 as their top marker genes. DIAPH3 has recently been shown to localize to the centromere during cell division, and we confirmed that expression of this gene is strongly associated with patient outcome in the TCGA. We postulate that mitotic populations play a role in generating the remaining ACC-specific cell types, including two major cell types expressing genes associated with the early stages of cholesterol synthesis (HMGCS1, HMGCR) and calcium signalling (CALN1, CADPS), respectively. These cell types are distributed in a mutually exclusive pattern across patients that reflect patterns of gene expression at the imprinted DLK1/MEG3 locus.
Conclusion: Our study provides insights into the cellular heterogeneity of ACC, revealing a hierarchical process of differentiation that could represent the basis for adrenocortical pathogenesis.
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Endocrine Abstracts
ISSN 1470-3947 (print) | ISSN 1479-6848 (online)
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