ARID1A and PI3-kinase pathway mutations in the endometrium drive epithelial transdifferentiation and collective invasion

Nature Communications
Mike R WilsonRonald L Chandler

Abstract

ARID1A and PI3-Kinase (PI3K) pathway alterations are common in neoplasms originating from the uterine endometrium. Here we show that monoallelic loss of ARID1A in the mouse endometrial epithelium is sufficient for vaginal bleeding when combined with PI3K activation. Sorted mutant epithelial cells display gene expression and promoter chromatin signatures associated with epithelial-to-mesenchymal transition (EMT). We further show that ARID1A is bound to promoters with open chromatin, but ARID1A loss leads to increased promoter chromatin accessibility and the expression of EMT genes. PI3K activation partially rescues the mesenchymal phenotypes driven by ARID1A loss through antagonism of ARID1A target gene expression, resulting in partial EMT and invasion. We propose that ARID1A normally maintains endometrial epithelial cell identity by repressing mesenchymal cell fates, and that coexistent ARID1A and PI3K mutations promote epithelial transdifferentiation and collective invasion. Broadly, our findings support a role for collective epithelial invasion in the spread of abnormal endometrial tissue.

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Citations

Nov 17, 2019·International Journal of Molecular Sciences·Pradip De, Nandini Dey
Dec 31, 2019·Human Reproduction·Mike R WilsonRonald L Chandler
Jun 24, 2020·Journal of Cellular Physiology·Bing-Jun ChenXin-Hua Liang
Jul 13, 2020·Cancer Science·Satoru KyoKentaro Nakayama
Jun 9, 2020·Gastric Cancer : Official Journal of the International Gastric Cancer Association and the Japanese Gastric Cancer Association·Leo YamadaKoji Kono
Jun 2, 2020·Frontiers in Oncology·Deborah P Lavin, Vijay K Tiwari
Nov 12, 2019·American Journal of Physiology. Gastrointestinal and Liver Physiology·Nazih L NakhoulSolange M Abdulnour-Nakhoul
Oct 20, 2020·Human Molecular Genetics·Jake J ReskeRonald L Chandler
Jan 9, 2021·Frontiers in Oncology·Jill AlldredgeFarah Rahmatpanah
Mar 27, 2021·Seminars in Cancer Biology·Khalid El BairiSaid Afqir
May 1, 2021·Cancers·Kazuaki TakahashiTakashi Kohno
Nov 25, 2021·Journal of Cancer Research and Clinical Oncology·Takeo YamamotoYoshinao Oda

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Methods Mentioned

BETA
immunoprecipitation
genotyping
PCR
flow cytometry
RNA-seq
ChIP
ChIP-seq
co-immunoprecipitation
transfection
Protein Assay

Software Mentioned

samtools view - f
ssGSEA
Scaffold
csaw
samtools
intersectBed
FastQC
ClusterProfiler
biomaRt
GSEA

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