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

Mike R Wilson,Ronald L Chandler,Jake J Reske,Richard E Leach,Ben Johnson,Ren-Wei Su,Jeanne Holladay,Genna E Wilber,Amanda L Patterson,Asgerally T Fazleabas,Hui Shen,Julie Koeman,Mary Rhodes,Niraj R Joshi,Jose M Teixeira,Marie Adams

doi:10.1038/s41467-019-11403-6

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.

Highlights

ARID1A and PI3-Kinase (PI3K) pathway alterations are common in neoplasms originating from the uterine endometrium
Co-existing PIK3CA mutation was significantly associated with ARID1A mutation, and a majority
For genes found in the Mak and Tong signature and the hallmark epithelial-to-mesenchymal transition (EMT) pathway, we identified an antagonistic relationship between siARID1A and PIK3CAH1047R, such that gene expression changes observed in siARID1A samples were reduced in siARID1A/PIK3CAH1047R samples (Fig. 6e, f)

Summary

Introduction

ARID1A and PI3-Kinase (PI3K) pathway alterations are common in neoplasms originating from the uterine endometrium. 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. Loss of ARID1A in complex atypical hyperplasia is associated with malignant transformation and concurrent EC15. ARID1A mutations are observed in 11% of endometriosis and >30% of EAOCs3,5,16,17 These data support a tumor suppressor role for ARID1A-containing SWI/SNF complexes in neoplasms originating from the endometrium

Methods

Results

Conclusion