Phosphoproteomic dysregulation promotes tumor proliferation in Cushing’s disease

Pituitary adenomas constitute up to 20% of primary brain tumors, yet somatic mutations are only found in 15% of pituitary adenomas. Epigenomic dysregulation has been proposed as a tumorigenic mechanism in pituitary adenomas causing Cushing’s disease (CD). We created paired datasets of human CD adenomas and en-route margin adult human pituitary glands, and assayed their chromatin accessibility, DNA methylation, transcriptomic, proteomic, and phospho-proteomic landscapes. In CD adenomas, we found epigenetic reactivation of a neurodevelopmental phosphoprotein program typically lost in the postnatal pituitary gland. CD cells overexpressed PPP1R17 , an endogenous inhibitor of the protein phosphatase PP2A. Mechanistically, PPP1R17 overexpression in normal murine pituitary cells recapitulated the adenoma phenotype, and the resulting hyperproliferation was reversed in a PP2A-dependent manner by fingolimod, an FDA-approved small molecule, both in vitro and in vivo. Our findings highlight kinase-phosphatase imbalance as a targetable mechanism in CD.

Authors

Institutions

Publication Details

Journal
Proceedings of the National Academy of Sciences
Published
2026-09-29
DOI
https://doi.org/10.1073/pnas.2528513123
Primary Topic
Pituitary Gland Disorders and Treatments
Type
article
Field-Weighted Citation Impact
0.00
Controls
|||
ALL TIME
JAN
FEB
MAR
APR
MAY
JUN
JUL
AUG
SEP
article

Phosphoproteomic dysregulation promotes tumor proliferation in Cushing’s disease

Christina Tatsi, Nasir Malik, Debjani Mandal, Joseph P. Steiner et al.
Proceedings of the National Academy of Sciences
Pituitary Gland Disorders and Treatments
article

Phosphoproteomic dysregulation promotes tumor proliferation in Cushing’s disease

Christina Tatsi, Nasir Malik, Debjani Mandal, Joseph P. Steiner, Susan Wray, Clarisse Quignon, Lynnette K. Nieman, Zied Abdullaev, Sheelu Varghese, Dustin Mullaney, David T. Asuzu, Kenneth Aldape, Diana Nwokoye, Dragan Maric, Prashant Chittiboina, Nikhil Ramavenkat, Yan Li, Kory R. Johnson, Abdel G. Elkahloun, Dhruval Bhatt, Daniela Tortoza Lopez
article en

Abstract

Pituitary adenomas constitute up to 20% of primary brain tumors, yet somatic mutations are only found in 15% of pituitary adenomas. Epigenomic dysregulation has been proposed as a tumorigenic mechanism in pituitary adenomas causing Cushing’s disease (CD). We created paired datasets of human CD adenomas and en-route margin adult human pituitary glands, and assayed their chromatin accessibility, DNA methylation, transcriptomic, proteomic, and phospho-proteomic landscapes. In CD adenomas, we found epigenetic reactivation of a neurodevelopmental phosphoprotein program typically lost in the postnatal pituitary gland. CD cells overexpressed PPP1R17 , an endogenous inhibitor of the protein phosphatase PP2A. Mechanistically, PPP1R17 overexpression in normal murine pituitary cells recapitulated the adenoma phenotype, and the resulting hyperproliferation was reversed in a PP2A-dependent manner by fingolimod, an FDA-approved small molecule, both in vitro and in vivo. Our findings highlight kinase-phosphatase imbalance as a targetable mechanism in CD.

Proceedings of the National Academy of SciencesVol. 123(40)
National Institutes of Health (US), National Institute of Diabetes and Digestive and Kidney Diseases (US), National Institute of Neurological Disorders and Stroke (US), National Cancer Institute (MY), National Cancer Institute (US), Eunice Kennedy Shriver National Institute of Child Health and Human Development (US), University of Virginia (US), The University of Texas Southwestern Medical Center (US)
Good health and well-being
Openalex Percentile: Top 12%
Pituitary Gland Disorders and Treatments
DOIOpen Access PDFOpenAlex
AI Navigator

Ask Laika to Summarize, Analyze, and Connect papers live on the map.

Summarize Papers & Methodologies

Extract key findings, datasets, and comparative methods across publications.

Benchmark Rankings & Visual Analytics

Rank top research institutions, authors, funders, topics, and journals by Field-Weighted Citation Impact (FWCI) and paper volume with instant charts.

Connect Distant Disciplines

Bridge topological clusters on the map to find hidden collaborative intersections.