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Dissecting the intra- and intertumoral heterogeneity of adrenocortical carcinoma by single-cell multi-omics analyses [II]

ABSTRACT: Adrenocortical carcinoma (ACC) is a rare but aggressive malignancy originating in the adrenal cortex, characterized by significant intra- and intertumoral heterogeneity. In this study, we employed a combination of whole-genome sequencing, single-cell RNA sequencing, T cell receptor sequencing, spatial transcriptome sequencing, and multiple fluorescent staining to construct a comprehensive multi-omics landscape of ACC. Our findings demonstrated that, although all tumor cells exhibited a "confused cell identity" feature, distinct subpopulations were present in each ACC patient. Among these, the LDLR+ and MKI67+ subpopulations expressed elevated levels of C1A signature genes and established robust communication with endothelial cells through NECTIN-PVR and NOTCH2-JAG pairs, both significantly associated with poor prognosis. Interestingly, the PCDH15+ subpopulations displayed moderate levels of both C1A signature genes and extracellular matrix related genes. On the other hand, the HLA-B+ and subpopulation exhibited the highest levels of antigen-processing related genes, a characteristic not previously reported. The amalgamation of these distinct subpopulations facilitated the stratification of ACC patients into subtypes with varying prognoses. Patients (Group II) dominated by LDLR+ and MKI67+ subpopulations exhibited the worst prognosis, while those (Group III) with a higher proportion of PCDH15+ subpopulation demonstrated the most favorable outcomes. Significantly, patients (Group I) with a higher prevalence of the HLA-B+ subpopulation also showed notably increased LAG3+ memory CD8 T cells, indicating their potential suitability for immunotherapy. Despite responding averagely to conventional treatment, this subgroup was predicted to be responsive to immunotherapy. Notably, one patient from Group I exhibited a positive response to camrelizumab treatment after relapse with mitotane, leading to a successful outcome, while two patients from Group II did not respond favorably. Our study offers insights into the single-cell level heterogeneity of ACC and provides valuable implications for precision treatments for this disease.

ORGANISM(S): Homo sapiens

PROVIDER: GSE252112 | GEO | 2025/12/26

REPOSITORIES: GEO

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Project description:Adrenocortical carcinoma (ACC) is a rare but aggressive malignancy originating in the adrenal cortex, characterized by significant intra- and intertumoral heterogeneity. In this study, we employed a combination of whole-genome sequencing, single-cell RNA sequencing, T cell receptor sequencing, spatial transcriptome sequencing, and multiple fluorescent staining to construct a comprehensive multi-omics landscape of ACC. Our findings demonstrated that, although all tumor cells exhibited a "confused cell identity" feature, distinct subpopulations were present in each ACC patient. Among these, the LDLR+ and MKI67+ subpopulations expressed elevated levels of C1A signature genes and established robust communication with endothelial cells through NECTIN-PVR and NOTCH2-JAG pairs, both significantly associated with poor prognosis. Interestingly, the PCDH15+ subpopulations displayed moderate levels of both C1A signature genes and extracellular matrix related genes. On the other hand, the HLA-B+ and subpopulation exhibited the highest levels of antigen-processing related genes, a characteristic not previously reported. The amalgamation of these distinct subpopulations facilitated the stratification of ACC patients into subtypes with varying prognoses. Patients (Group II) dominated by LDLR+ and MKI67+ subpopulations exhibited the worst prognosis, while those (Group III) with a higher proportion of PCDH15+ subpopulation demonstrated the most favorable outcomes. Significantly, patients (Group I) with a higher prevalence of the HLA-B+ subpopulation also showed notably increased LAG3+ memory CD8 T cells, indicating their potential suitability for immunotherapy. Despite responding averagely to conventional treatment, this subgroup was predicted to be responsive to immunotherapy. Notably, one patient from Group I exhibited a positive response to camrelizumab treatment after relapse with mitotane, leading to a successful outcome, while two patients from Group II did not respond favorably. Our study offers insights into the single-cell level heterogeneity of ACC and provides valuable implications for precision treatments for this disease.

Project description:Adrenocortical carcinoma (ACC) is an aggressive malignancy with a low but variable overall survival rate. Even after complete tumor resection, over half of patients develop recurrent disease. Long noncoding RNAs (lncRNAs) have been found to be involved in cancer initiation/progression and as markers of cancer prognosis. The role of lncRNAs in ACC is poorly understood. Thus, in this study we performed lncRNA expression profiling in ACC, adrenocortical adenoma (ACA) and normal adrenal cortex (NAC). Total RNA was extracted from fresh frozen tissue samples (11 ACA, nine ACC and five NAC samples) with histopathological confirmed diagnosis. ArrayStar Human LncRNA/mRNA Expression Microarray V3.0 was used for transcriptome analysis. Differentially expressed lncRNAs were validated using TaqMan real-time quantitative PCR in a validation cohort including an additional 10 ACCs. The ACC dataset from the Cancer Genome Atlas (TCGA) project was used to evaluate the prognostic utility of lncRNAs found to be differentially expressed in ACC. Survival curves were plotted by Kaplan-Meier analysis, and differences in survival rates were assessed using a log-rank test. P < 0.05 was considered significant. Gene Set Enrichment Analysis (GSEA) was performed to identify lncRNA-associated biological signaling pathways. Unsupervised hierarchical and heat map clustering showed distinct clustering of ACC samples compared with NAC and ACA samples by lncRNA expression profiles. A total of 874 lncRNAs were differentially expressed between ACC and NAC, including known carcinogenesis-related lncRNAs such as HOTTIP, HOXA11-AS1, CRNDE, LINC00271 and TBXAS1. One thousand seventy-six lncRNAs were differentially expressed between ACC and ACA. LINC00271 was a prognostic marker, with patients with low LINC00271 expression surviving significantly shorter than patients with a high LINC00271 expression. Median survival time (MST) for the low-expression group was 1788 days, whereas the MST was not reached for the high-expression group (P < 0.019). Importantly, low LINC00271 expression was positively associated with WNT signaling, cell cycle, chromosome segregation and tissue morphogenesis pathways. ACC has a distinct lncRNA expression profile. LINC00271 is a prognostic marker in ACC and is involved in biological pathways commonly dysregulated in ACC.

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Dissecting the intra- and intertumoral heterogeneity of adrenocortical carcinoma by single-cell multi-omics analyses [II]

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