Epigenetic feedback and stochastic partitioning during cell division can drive resistance to EMT

Abstract

Epithelial-mesenchymal transition (EMT) and its reverse process mesenchymal-epithelial transition (MET) are central to metastatic aggressiveness and therapy resistance in solid tumors. While molecular determinants of both processes have been extensively characterized, the heterogeneity in the response of tumor cells to EMT and MET inducers has come into focus recently, and has been implicated in the failure of anti-cancer therapies. Recent experimental studies have shown that some cells can undergo an irreversible EMT depending on the duration of exposure to EMT-inducing signals. While the irreversibility of MET, or equivalently, resistance to EMT, has not been studied in as much detail, evidence supporting such behavior is slowly emerging. Here, we identify two possible mechanisms that can underlie resistance of cells to undergo EMT: epigenetic feedback in ZEB1/GRHL2 feedback loop and stochastic partitioning of biomolecules during cell division. Identifying the ZEB1/GRHL2 axis as a key determinant of epithelial-mesenchymal plasticity across many cancer types, we use mechanistic mathematical models to show how GRHL2 can be involved in both the abovementioned processes, thus driving an irreversible MET. Our study highlights how an isogenic population may contain subpopulation with varying degrees of susceptibility or resistance to EMT, and proposes a next set of questions for detailed experimental studies characterizing the irreversibility of MET/resistance to EMT.

Systems-level network modeling deciphers the master regulators of phenotypic plasticity and heterogeneity in melanoma

“…These results suggest that the proliferative and invasive phenotype genes tend to form two ‘teams’ of mutually opposing players that can govern the emergence of phenotypic plasticity and heterogeneity in melanoma. Such ‘teams’ have been witnessed between EMT-inducing and EMT-inhibiting factors (Jia et al, 2020b), as well as those between master regulators of ‘classic’ and ‘variant’ subtypes in small cell lung cancer (Chauhan et al, 2020), elucidating a potential common design principle for regulatory networks involved in cancer cell plasticity.…”

Epigenetic Regulation of Epithelial to Mesenchymal Transition in the Cancer Metastatic Cascade: Implications for Cancer Therapy

“…These emerging studies have revealed global epigenetic alterations and identified major factors including Zeb1, RUNX2, GRHL, and CTCF involved in reversible or stabilized EMT/MET in multiple cell lines ( 69 , 99 – 102 ). Besides, recent mathematical models proposed conceptually that epigenetic process may play a significant role in the irreversibility of EMT and MET, where epigenetic feedback-mediated suppression on miR-200 by Zeb1 led to the irreversibility of EMT, while epigenetic feedback-mediated suppression on Zeb1 by GRHL2 resulted in the irreversibility of MET ( 95 , 103 ). Yet this irreversible MET has been proved to be unlocked by epigenetic modification in the preliminary experiment ( 95 , 104 ).…”

KLF4 induces Mesenchymal - Epithelial Transition (MET) by suppressing multiple EMT-inducing transcription factors

“…blocking access to ZEB1 promoter for EMT inducers) in inhibiting ZEB1 can enable irreversible MET, i.e. resistance of cells to undergo EMT [67,68]. Here, we assessed the impact of KLF4-mediated epigenetic silencing of SNAIL (i.e.…”