A human ACTH-secreting corticotroph tumoroid model
Background: Cushing disease (CD), although rare, is a life-threatening disorder caused by an adrenocorticotropic hormone (ACTH)-secreting pituitary adenoma, which leads to excess adrenal-derived cortisol. Efficacious and safe medical therapies that control both hormonal hypersecretion and pituitary...
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| Format: | Article |
| Language: | English |
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Elsevier
2021-04-01
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| Series: | EBioMedicine |
| Subjects: | |
| Online Access: | http://www.sciencedirect.com/science/article/pii/S2352396421000876 |
| _version_ | 1818410482235604992 |
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| author | Dongyun Zhang Willy Hugo Peter Redublo Hui Miao Marvin Bergsneider Marilene B. Wang Won Kim William H. Yong Anthony P. Heaney |
| author_facet | Dongyun Zhang Willy Hugo Peter Redublo Hui Miao Marvin Bergsneider Marilene B. Wang Won Kim William H. Yong Anthony P. Heaney |
| author_sort | Dongyun Zhang |
| collection | DOAJ |
| description | Background: Cushing disease (CD), although rare, is a life-threatening disorder caused by an adrenocorticotropic hormone (ACTH)-secreting pituitary adenoma, which leads to excess adrenal-derived cortisol. Efficacious and safe medical therapies that control both hormonal hypersecretion and pituitary corticotroph tumor growth remain an unmet need in the management of CD. Translational research in pituitary tumors has been significantly hampered by limited quantities of surgically resected tissue for ex vivo studies, and unavailability of human pituitary tumor cell models. Methods: To characterize human corticotroph tumors at the cellular level, we employed single cell RNA-sequencing (scRNA-seq) to study 4 surgically resected tumors. We also used microarrays to compare individualized paired consecutive culture passages to understand transcriptional shifts as in vitro cultures lost ACTH secretion. Based on these findings, we then modified our in vitro culture methods to develop sustained ACTH-secreting human corticotroph tumoroid cultures. Findings: scRNA-seq identified 4 major cell populations, namely corticotroph tumor (73.6%), stromal (11.2%), progenitor (8.3%), and immune cells (6.8%). Microarray analysis revealed striking changes in extracellular matrix, cell adhesion and motility-related genes concordant with loss of ACTH secretion during conventional 2D culture. Based on these findings, we subsequently defined a series of crucial culture nutrients and scaffold modifications that provided a more favorable trophic and structural environment that could maintain ACTH secretion in in vitro human corticotroph tumor cultures for up to 4 months. Interpretation: Our human corticotroph tumoroid model is a significant advance in the field of pituitary tumors and will further enable translational research studies to identify critically needed therapies for CD. Funding: This work was partly funded by NCI P50-CA211015 and the Warley Trust Foundation. |
| first_indexed | 2024-12-14T10:16:13Z |
| format | Article |
| id | doaj.art-2601596e7f584ac4b65e0bb080bf7b79 |
| institution | Directory Open Access Journal |
| issn | 2352-3964 |
| language | English |
| last_indexed | 2024-12-14T10:16:13Z |
| publishDate | 2021-04-01 |
| publisher | Elsevier |
| record_format | Article |
| series | EBioMedicine |
| spelling | doaj.art-2601596e7f584ac4b65e0bb080bf7b792022-12-21T23:06:48ZengElsevierEBioMedicine2352-39642021-04-0166103294A human ACTH-secreting corticotroph tumoroid modelDongyun Zhang0Willy Hugo1Peter Redublo2Hui Miao3Marvin Bergsneider4Marilene B. Wang5Won Kim6William H. Yong7Anthony P. Heaney8Departments of Medicine, David Geffen School of Medicine, University of California, Los Angeles, United StatesDepartments of Medicine, David Geffen School of Medicine, University of California, Los Angeles, United StatesDepartments of Medicine, David Geffen School of Medicine, University of California, Los Angeles, United StatesDepartments of Medicine, David Geffen School of Medicine, University of California, Los Angeles, United StatesDepartments of Neurosurgery, David Geffen School of Medicine, University of California, Los Angeles, United StatesDepartments of Head and Neck Surgery, David Geffen School of Medicine, University of California, Los Angeles, United StatesDepartments of Neurosurgery, David Geffen School of Medicine, University of California, Los Angeles, United StatesDepartments of Pathology and Lab Medicine, David Geffen School of Medicine, University of California, Los Angeles, United StatesDepartments of Medicine, David Geffen School of Medicine, University of California, Los Angeles, United States; Departments of Neurosurgery, David Geffen School of Medicine, University of California, Los Angeles, United States; Corresponding author.Background: Cushing disease (CD), although rare, is a life-threatening disorder caused by an adrenocorticotropic hormone (ACTH)-secreting pituitary adenoma, which leads to excess adrenal-derived cortisol. Efficacious and safe medical therapies that control both hormonal hypersecretion and pituitary corticotroph tumor growth remain an unmet need in the management of CD. Translational research in pituitary tumors has been significantly hampered by limited quantities of surgically resected tissue for ex vivo studies, and unavailability of human pituitary tumor cell models. Methods: To characterize human corticotroph tumors at the cellular level, we employed single cell RNA-sequencing (scRNA-seq) to study 4 surgically resected tumors. We also used microarrays to compare individualized paired consecutive culture passages to understand transcriptional shifts as in vitro cultures lost ACTH secretion. Based on these findings, we then modified our in vitro culture methods to develop sustained ACTH-secreting human corticotroph tumoroid cultures. Findings: scRNA-seq identified 4 major cell populations, namely corticotroph tumor (73.6%), stromal (11.2%), progenitor (8.3%), and immune cells (6.8%). Microarray analysis revealed striking changes in extracellular matrix, cell adhesion and motility-related genes concordant with loss of ACTH secretion during conventional 2D culture. Based on these findings, we subsequently defined a series of crucial culture nutrients and scaffold modifications that provided a more favorable trophic and structural environment that could maintain ACTH secretion in in vitro human corticotroph tumor cultures for up to 4 months. Interpretation: Our human corticotroph tumoroid model is a significant advance in the field of pituitary tumors and will further enable translational research studies to identify critically needed therapies for CD. Funding: This work was partly funded by NCI P50-CA211015 and the Warley Trust Foundation.http://www.sciencedirect.com/science/article/pii/S2352396421000876Adrenocorticotropic hormone (ACTH)Cushing disease (CD)3D cultureProopiomelanocortin (POMC) |
| spellingShingle | Dongyun Zhang Willy Hugo Peter Redublo Hui Miao Marvin Bergsneider Marilene B. Wang Won Kim William H. Yong Anthony P. Heaney A human ACTH-secreting corticotroph tumoroid model EBioMedicine Adrenocorticotropic hormone (ACTH) Cushing disease (CD) 3D culture Proopiomelanocortin (POMC) |
| title | A human ACTH-secreting corticotroph tumoroid model |
| title_full | A human ACTH-secreting corticotroph tumoroid model |
| title_fullStr | A human ACTH-secreting corticotroph tumoroid model |
| title_full_unstemmed | A human ACTH-secreting corticotroph tumoroid model |
| title_short | A human ACTH-secreting corticotroph tumoroid model |
| title_sort | human acth secreting corticotroph tumoroid model |
| topic | Adrenocorticotropic hormone (ACTH) Cushing disease (CD) 3D culture Proopiomelanocortin (POMC) |
| url | http://www.sciencedirect.com/science/article/pii/S2352396421000876 |
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