MAPK14/p38α shapes the molecular landscape of endometrial cancer and promotes tumorigenic characteristics

Sayali Joseph; Xingyuan Zhang; Gaith N Droby; Di Wu; Victoria Bae-Jump; Scott Lyons; Angie Mordant; Allie Mills; Laura Herring; Blake Rushing; Jessica L Bowser; Cyrus Vaziri

doi:10.1016/j.celrep.2024.115104

MAPK14/p38α shapes the molecular landscape of endometrial cancer and promotes tumorigenic characteristics

Cell Rep. 2024 Dec 20;44(1):115104. doi: 10.1016/j.celrep.2024.115104. Online ahead of print.

Authors

Sayali Joseph¹, Xingyuan Zhang², Gaith N Droby³, Di Wu⁴, Victoria Bae-Jump⁵, Scott Lyons⁶, Angie Mordant⁶, Allie Mills⁶, Laura Herring⁶, Blake Rushing⁷, Jessica L Bowser⁸, Cyrus Vaziri⁹

Affiliations

¹ Department of Pathology and Laboratory Medicine, University of North Carolina, Chapel Hill, NC 27599, USA.
² Department of Pathology and Laboratory Medicine, University of North Carolina, Chapel Hill, NC 27599, USA; Department of Biostatistics and Bioinformatics, Duke University School of Medicine, Durham, NC 27710, USA.
³ Department of Pathology and Laboratory Medicine, University of North Carolina, Chapel Hill, NC 27599, USA; Curriculum in Genetics and Molecular Biology, University of North Carolina, Chapel Hill, NC 27599, USA.
⁴ Department of Biostatistics, University of North Carolina, Chapel Hill, NC 27599, USA.
⁵ Lineberger Comprehensive Cancer Center, University of North Carolina, Chapel Hill, NC 27599, USA.
⁶ Department of Pharmacology, UNC Proteomics Core Facility, University of North Carolina, Chapel Hill, NC 27599, USA.
⁷ Department of Pathology and Laboratory Medicine, University of North Carolina, Chapel Hill, NC 27599, USA; Lineberger Comprehensive Cancer Center, University of North Carolina, Chapel Hill, NC 27599, USA; Nutrition Research Institute, University of North Carolina at Chapel Hill, Kannapolis, NC 28081, USA; Department of Nutrition, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA.
⁸ Department of Pathology and Laboratory Medicine, University of North Carolina, Chapel Hill, NC 27599, USA; Lineberger Comprehensive Cancer Center, University of North Carolina, Chapel Hill, NC 27599, USA. Electronic address: [email protected].
⁹ Department of Pathology and Laboratory Medicine, University of North Carolina, Chapel Hill, NC 27599, USA; Curriculum in Genetics and Molecular Biology, University of North Carolina, Chapel Hill, NC 27599, USA; Lineberger Comprehensive Cancer Center, University of North Carolina, Chapel Hill, NC 27599, USA. Electronic address: [email protected].

PMID: 39708320
DOI: 10.1016/j.celrep.2024.115104

Abstract

The molecular underpinnings of high-grade endometrial carcinoma (HGEC) metastatic growth and survival are poorly understood. Here, we show that ascites-derived and primary tumor HGEC cell lines in 3D spheroid culture faithfully recapitulate key features of malignant peritoneal effusion and exhibit fundamentally distinct transcriptomic, proteomic, and metabolomic landscapes compared with conventional 2D monolayers. Using a genetic screening platform, we identify MAPK14 (which encodes the protein kinase p38α) as a specific requirement for HGEC in spheroid culture. MAPK14/p38α has broad roles in programming the phosphoproteome, transcriptome, and metabolome of HGEC spheroids, yet has negligible impact on monolayer cultures. MAPK14 promotes tumorigenicity in vivo and is specifically required to sustain a sub-population of spheroid cells that is enriched in cancer stemness markers. Therefore, spheroid growth of HGEC activates unique biological programs, including p38α signaling, that cannot be captured using 2D culture models and are highly relevant to malignant disease pathology.

Keywords: 3D spheroids; CP: Cancer; CRISPR-Cas9 screen; MAPK14; NDRG1; endometrial cancer; kinome; p38α.