A human ACTH-secreting corticotroph tumoroid model

Dongyun Zhang; Willy Hugo; Peter Redublo; Hui Miao; Marvin Bergsneider; Marilene B. Wang; Won Kim; William H. Yong; Anthony P. Heaney

EBioMedicine (Apr 2021)

A human ACTH-secreting corticotroph tumoroid model

Dongyun Zhang,
Willy Hugo,
Peter Redublo,
Hui Miao,
Marvin Bergsneider,
Marilene B. Wang,
Won Kim,
William H. Yong,
Anthony P. Heaney

Affiliations

Dongyun Zhang: Departments of Medicine, David Geffen School of Medicine, University of California, Los Angeles, United States
Willy Hugo: Departments of Medicine, David Geffen School of Medicine, University of California, Los Angeles, United States
Peter Redublo: Departments of Medicine, David Geffen School of Medicine, University of California, Los Angeles, United States
Hui Miao: Departments of Medicine, David Geffen School of Medicine, University of California, Los Angeles, United States
Marvin Bergsneider: Departments of Neurosurgery, David Geffen School of Medicine, University of California, Los Angeles, United States
Marilene B. Wang: Departments of Head and Neck Surgery, David Geffen School of Medicine, University of California, Los Angeles, United States
Won Kim: Departments of Neurosurgery, David Geffen School of Medicine, University of California, Los Angeles, United States
William H. Yong: Departments of Pathology and Lab Medicine, David Geffen School of Medicine, University of California, Los Angeles, United States
Anthony P. Heaney: Departments 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.

Journal volume & issue: Vol. 66
p. 103294

Abstract

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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.

Published in EBioMedicine

ISSN: 2352-3964 (Online)
Publisher: Elsevier
Country of publisher: Netherlands
LCC subjects: Medicine: Medicine (General)
Website: http://www.journals.elsevier.com/ebiomedicine/

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