Mouse Models Recapitulating Human Adrenocortical Tumors: What Is Lacking?

Leccia, F.; Batisse-Lignier, Marie; Sahut‐Barnola, Isabelle; Val, Pierre; Lefrançois‐Martinez, Anne‐Marie; Martinez, Antoine

doi:10.3389/fendo.2016.00093

Cited by 16 publications

(11 citation statements)

References 134 publications

(173 reference statements)

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“…Similarly, mouse models are instrumental in dissecting the pathogenic mechanisms in adreno-cortical tumorigenesis and to establish the functional significance of the mutations and alterations identified in genomic studies of adrenal tumors (i.e [28,33]. for ACC, and reviewed in [20,34]). However, it is recognized that some models do not completely phenocopy the human disease in terms of metastatic properties or penetrance [34].…”

Section: Discussionmentioning

confidence: 99%

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DLK1/PREF1 marks a novel cell population in the human adrenal cortex

Hadjidemetriou

Mariniello

Ruiz-Babot

et al. 2019

The Journal of Steroid Biochemistry and Molecular Biology

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The adrenal cortex governs fundamental metabolic processes though synthesis of glucocorticoid, miner-alocorticoids and androgens. Studies in rodents have demonstrated that the cortex undergoes a self-renewal process and that capsular/subcapsular stem/progenitor cell pools differentiate towards functional steroidogenic cells supporting the dynamic centripetal streaming of adrenocortical cells throughout life. We previously demonstrated that the Notch atypical ligand Delta-like homologue 1 (DLK1)/preadipocyte factor 1 (PREF1) is expressed in subcapsular Sf1 and Shh-positive, CYP11B1-negative and CYP11B2-partially positive cortical progenitor cells in rat adrenals, and that secreted DLK1 can modulate GLI1 expression in H295R cells. Here we show that the human adrenal cortex remodels with age to generate clusters of relatively undifferentiated cells expressing DLK1. These clusters (named DLK1-expressing cell clusters or *

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Section: Discussionmentioning

confidence: 99%

“…for ACC, and reviewed in [20,34]). However, it is recognized that some models do not completely phenocopy the human disease in terms of metastatic properties or penetrance [34].…”

Section: Discussionmentioning

confidence: 99%

DLK1/PREF1 marks a novel cell population in the human adrenal cortex

Hadjidemetriou

Mariniello

Ruiz-Babot

et al. 2019

The Journal of Steroid Biochemistry and Molecular Biology

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“…These results are likely due, in part, to the lack of mouse models that recapitulate the genetics of ACC. Thus, there is an urgent need to develop relevant mouse models of malignant ACC in order to test new therapeutic approaches [ 7 , 8 ].…”

Section: Introductionmentioning

confidence: 99%

Wnt/β-catenin activation cooperates with loss of p53 to cause adrenocortical carcinoma in mice

et al. 2020

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Adrenocortical carcinoma (ACC) is a rare and aggressive malignancy with limited therapeutic options. The lack of mouse models that recapitulate the genetics of ACC has hampered progress in the field. We analyzed The Cancer Genome Atlas (TCGA) dataset for ACC and found that patients harboring alterations in both p53/Rb and Wnt/β-catenin signaling pathways show a worse prognosis compared with patients that harbored alterations in only one. To model this, we utilized the Cyp11b2(AS) Cre mouse line to generate mice with adrenocortical-specific Wnt/β-catenin activation, Trp53 deletion, or the combination of both. Mice with targeted Wnt/β-catenin activation or Trp53 deletion showed no changes associated with tumor formation. In contrast, alterations in both pathways led to ACC with pulmonary metastases. Similar to ACCs in humans, these tumors produced increased levels of corticosterone and aldosterone and showed a high proliferation index. Gene expression analysis revealed that mouse tumors exhibited downregulation of Star and Cyp11b1 and upregulation of Ezh2 , similar to ACC patients with a poor prognosis. Altogether, these data show that altering both Wnt/β-catenin and p53/Rb signaling is sufficient to drive ACC in mouse. This autochthonous model of ACC represents a new tool to investigate the biology of ACC and to identify new treatment strategies.

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“…Our understanding of the development and self-renewal of the adrenal cortex throughout life is informed mostly by rodent studies and by monogenic conditions affecting the development of the adrenal cortex. In addition, animal models of adrenal oncogenesis exist with heterogeneous penetrance of tumour formation (Basham et al 2016, Leccia et al 2016.…”

Section: Self-renewal and Signalling In The Adrenal Cortexmentioning

confidence: 99%

Pathobiology and genetics of adrenocortical carcinoma

Pittaway

Guasti

2019

Journal of Molecular Endocrinology

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Adrenocortical carcinoma (ACC) is a rare malignancy with an incidence worldwide of 0.7-2.0 cases/million/year. Initial staging is the most important factor in determining prognosis. If diagnosed early, surgical resection +/- adjuvant treatment can lead to five-year survival of up to 80%. However, often it is diagnosed late and in advanced disease five-year survival is <15% with a high recurrence rate even after radical surgery. The mainstay of adjuvant treatment is with the drug mitotane. Mitotane has a specific cytotoxic effect on steroidogenic cells of the adrenal cortex but despite this progression through treatment is common. Developments in genetic analysis in the form of next-generation sequencing, aided by bioinformatics, have enabled high-throughput molecular characterisation of these tumours. This, in addition to a better appreciation of the processes of physiological, homeostatic self-renewal of the adrenal cortex has furthered our understanding of the pathogenesis of this malignancy. In this review, we have detailed the pathobiology and genetic alterations in adrenocortical carcinoma through integrating current understanding of homeostasis and self-renewal in the normal adrenal cortex with molecular profiling of tumours from recent genetic analyses. Improved understanding of the mechanisms involved in self-renewal and stem cell hierarchy in normal human adrenal cortices, together with the identification of cell populations likely to be co-opted by oncogenic mutations, will enable further progress in the definition of the molecular pathways involved in the pathogenesis of ACC. The combination of these advances eventually will lead to the development of novel, effective and personalised strategies to eradicate molecularly annotated ACCs.

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Mouse Models Recapitulating Human Adrenocortical Tumors: What Is Lacking?

Cited by 16 publications

References 134 publications

DLK1/PREF1 marks a novel cell population in the human adrenal cortex

DLK1/PREF1 marks a novel cell population in the human adrenal cortex

Wnt/β-catenin activation cooperates with loss of p53 to cause adrenocortical carcinoma in mice

Pathobiology and genetics of adrenocortical carcinoma

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