Epigenetic Switch-Induced Viral Mimicry Evasion in Chemotherapy-Resistant Breast Cancer
Authors: Yunchi Ingrid Kao
Xiaojing Liu
Evelyne Lima-Fernandes
Mathieu Lupien
Morag Park
Paul Guilhamon
Alexandra N Fedor
Giacomo Grillo
Seyed Ali Madani Tonekaboni
Alex Murison
Ilias Ettayebi
Constanza Martinez
Cheryl H Arrowsmith
Hellen Kuasne
Paul Savage
Daniel D De Carvalho
Geneviève Deblois
Benjamin Haibe-Kains
David W Cescon
Jason W Locasale
Felicia Tai
Anne-Marie Fortier
Wail Ba-Alawi
Journal: Cancer Discovery (2020)
Discipline: CLINICAL MEDICINE
Keywords: Tumor progression; resistant cancer cells; persister cancer cells; viral mimicry response; taxane-resistant
Affiliations: Princess Margaret Cancer Centre, University Health Network, Toronto, Ontario, Canada., Institute for Research in Immunology and Cancer, Université de Montréal, Montréal, Quebec, Canada., Faculté de Pharmacie, Université de Montréal, Montréal, Quebec, Canada., Princess Margaret Cancer Centre., Goodman Cancer Research Centre, McGill University, Montréal, Quebec, Canada., Department of Medical Biophysics, University of Toronto, Toronto, Ontario, Canada., Department of Pharmacology and Cancer Biology, Duke University School of Medicine, Durham, North Carolina., Structural Genomics Consortium, Toronto, Ontario, Canada., Department of Computer Sciences, University of Toronto, Toronto, Ontario, Canada., Princess Margaret Cancer Centre, University Health Network, Toronto, Ontario, Canada. ., Ontario Institute for Cancer Research, Toronto, Ontario, Canada.

Abstract:  Tumor progression upon treatment arises from preexisting resistant cancer cells and/or adaptation of persister cancer cells committing to an expansion phase. Here, we show that evasion from viral mimicry response allows the growth of taxane-resistant triple-negative breast cancer (TNBC). This is enabled by an epigenetic state adapted to taxane-induced metabolic stress, where DNA hypomethylation over loci enriched in transposable elements (TE) is compensated by large chromatin domains of H3K27me3 to warrant TE repression. This epigenetic state creates a vulnerability to epigenetic therapy against EZH2, the H3K27me3 methyltransferase, which alleviates TE repression in taxane-resistant TNBC, leading to double-stranded RNA production and growth inhibition through viral mimicry response. Collectively, our results illustrate how epigenetic states over TEs promote cancer progression under treatment and can inform about vulnerabilities to epigenetic therapy. SIGNIFICANCE: Drug-resistant cancer cells represent a major barrier to remission for patients with cancer. Here we show that drug-induced metabolic perturbation and epigenetic states enable evasion from the viral mimicry response induced by chemotherapy in TNBC. These epigenetic states define a vulnerability to epigenetic therapy using EZH2 inhibitors in taxane-resistant TNBC.See related commentary by Janin and Esteller, p. 1258.This article is highlighted in the In This Issue feature, p. 1241. 

Retracted: No

PubPeer comments:
 Nice work. As you mentioned, H3K27me3 is a mark of heterochromatin. I am just curious that what is the initial chromatin states of parental cell v.s. resistant cells. Is it also heterochromatin (which means the cells try to maintain their closed chromatin states) or euchromatin (which means the cell repress the TE expression by condensing their chromatin)? , 
 #1 DNA methylation levels are high in parental cells compared to resistant cells over resistant specific H3K27me3 LOCKs (see Figure 3J for an example). ,