Biology subjects

Sbiera, S.

Publications and source records attributed to Sbiera, S..

4 recordsLinked to original sources

bioRxiv2025

Autocrine glucocorticoid signaling in hormonally active cancer induces antigen expression for immunotherapy

Exogenous glucocorticoids (GCs) suppress T cell-based immunotherapy, yet the consequences of endogenous GCs produced or regenerated by tumours remain poorly understood. Here, we show that tumour-derived GCs couple immune evasion to therapeutic antigenicity. In adrenocortical carcinoma, autonomous GC production activates hGR-STAT3 signaling to increase the surface antigen ROR1. This creates an immunological paradox in which GC excess promotes therapeutic antigen expression while suppressing T cell-mediated antitumor activity. Selective hGR-knockout renders ROR1 CAR-T cells GC-resistant while preserving GC-driven ROR1 expression in tumor cells, resulting in durable tumor control in vivo. Non-endocrine pancreatic and triple-negative breast cancers recreate this circuit through HSD11B1-mediated GC recycling, which is further induced by CAR-T cell-derived cytokines under immune pressure. Thus, GC-resistant CAR-T cells exploit a tumor-derived endocrine program that couples immune suppression to therapeutic antigenicity.

cancer biology↗

bioRxiv2024

Dlk1 is a novel adrenocortical stem/progenitor cell marker that predicts malignancy in adrenocortical carcinoma

Disruption of processes involved in tissue development and homeostatic self-renewal is increasingly implicated in cancer initiation, progression, and recurrence. The adrenal cortex is a dynamic tissue that undergoes life-long turnover. Here, using genetic fate mapping and murine adrenocortical carcinoma (ACC) models, we have identified a population of adrenocortical stem cells that express delta-like non-canonical Notch ligand 1 (DLK1). These cells are active during development, near dormant postnatally but are re-expressed in ACC. In a study of over 200 human ACC samples, we have shown DLK1 expression is ubiquitous and is an independent prognostic marker of recurrence-free survival. Paradoxically, despite its progenitor role, spatial transcriptomic analysis has identified DLK1 expressing cell populations to have increased steroidogenic potential in human ACC, a finding also observed in four human and one murine ACC cell lines. Finally, the cleavable DLK1 ectodomain is measurable in patients serum and can discriminate between ACC and other adrenal pathologies with high sensitivity and specificity to aid in diagnosis and follow-up of ACC patients. These data demonstrate a prognostic role for DLK1 in ACC, detail its hierarchical expression in homeostasis and oncogenic transformation and propose a role for its use as a biomarker in this malignancy. Graphical abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=160 SRC="FIGDIR/small/609117v1_ufig1.gif" ALT="Figure 1"> View larger version (51K): org.highwire.dtl.DTLVardef@12aba74org.highwire.dtl.DTLVardef@374daaorg.highwire.dtl.DTLVardef@cbdc37org.highwire.dtl.DTLVardef@1e6aeac_HPS_FORMAT_FIGEXP M_FIG C_FIG Statement of significanceThis study presents DLK1 as a novel biomarker in ACC with opportunities for use in the diagnosis, prognosis and longitudinal follow up of patients. DLK1, a marker of adrenocortical stem cells, is re-expressed in ACC, is measurable in patients serum and is associated with increased malignancy.

cancer biology↗

bioRxiv2023

Cellular landscape of adrenocortical carcinoma at single-nuclei resolution

Adrenocortical carcinoma (ACC) is a rare yet devastating tumour of the adrenal gland with a molecular pathology that remain incompletely understood. To gain novel insights into the cellular landscape of ACC, we generated single-nuclei RNA sequencing (snRNA-seq) data sets from twelve ACC tumour samples and analysed these alongside a previously published snRNA-seq data set from normal adrenal glands (NAGs). We find 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 identifies three separate groups of ACC samples that are characterised by different relative compositions of adrenocortical cell types, including two populations (ACC 1 and ACC 2) that are specifically enriched in the most aggressive tumours and display hallmarks of the epithelial to mesenchymal transition (EMT) and dysregulated steroidogenesis, respectively. In addition to cell types associated with hypoxic and metabolic signatures (ACC 3 and ACC 4) prevalent among less-aggressive tumours, we also identified and validated a population of mitotically active adrenocortical cells (ACC M) strongly overexpressing genes POLQ and DIAPH3 that possibly supports the expansion of malignant cell lineages. The smallest identified ACC specific cell type, ACC 5, displays characteristics of increased proliferation and growth factor signalling, and is therefore a potential progenitor-like or cell-of-origin candidate for the different lineages involved in adrenocortical carcinogenesis. Intriguingly, linage tracing suggests the fate adopted by malignant adrenocortical cells upon differentiation appears to be at least partly associated with the copy number or allelic balance state of the imprinted DLK1/MEG3 genomic locus, which we verified by assessing DNA methylation status among samples from the three groups of tumours defined by their different cell type compositions. Our results therefore provide new insights into the cellular heterogeneity of ACC, indicating that genetic perturbations to a hierarchical cellular differentiation mechanism underlying healthy adrenocortical renewal and zonation may explain the molecular basis for disease pathogenesis.

cancer biology↗

bioRxiv2022

Cell Atlas at Single-Nuclei Resolution of the Adult Human Adrenal Gland and Adrenocortical Adenomas

The human adrenal gland is a complex endocrine tissue. Developmental studies on this tissue have been limited to animal models or human foetus. Here, we present a cell atlas analysis of the adult human normal adrenal gland, combining single-nuclei RNA sequencing and spatial transcriptome data to reconstruct adrenal gland development and tumourigenesis. We identified two populations of potential progenitor cells resident within the adrenal cortex: adrenocortical progenitors NR2F2+-ID1+ cells, located within and underneath the capsule, and medullary progenitors SYT1+-CHGA- cells, located in islets in the subcapsular region. Using pseudotime analyses, we provided evidence of the centripetal nature of adrenocortical cell development and of the essential role played by the Wnt/{beta}-catenin pathway in the adrenocortical self-renewal. By comparing transcriptional profiles of cells of normal adrenal glands and adrenocortical adenomas we revealed a high heterogeneity with six adenoma-specific clusters. Overall, our results give insights into adrenal plasticity and mechanisms underlying adrenocortical tumourigenesis.

physiology↗