OVOL1/2: Drivers of Epithelial Differentiation in Development, Disease, and Reprogramming

Saxena, Kritika; Srikrishnan, Syamanthak; Celià-Terrassa, Toni; Jolly, Mohit Kumar

doi:10.1159/000511383

Cited by 27 publications

(19 citation statements)

References 68 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…We observed that these PSFs maintained the enrichment of hybrid E/M phenotypes in stem-like traits, endorsing the robustness of this association. Consistently, many of these PSFs have been reported to play a functional role in maintaining more epithelial phenotypes (e, he) as well as stemness in experiments in cancer cell lines and in cellular reprogramming contexts involving the modulation of EMP [ 53 , 77 , 78 ]. GRHL2 and OVOL2 have also been proposed as MET-inducing transcription factors (MET-TFs), but our simulations suggest that their ability to induce a “complete” MET need not be universal.…”

Section: Discussionmentioning

confidence: 73%

“…In addition to being thought of as PSFs, GRHL2 and OVOL1/2 have been considered as Mesenchymal-Epithelial Transition (MET)-inducing transcription factors (MET-TFs), as their overexpression in carcinomas is capable of upregulating the expression levels of E-cadherin and/or revert EMT [ 50 , 51 , 52 , 53 , 54 ] as well as other EMT-associated traits, such as anoikis resistance, metabolic reprogramming [ 55 ], and immune evasion [ 56 ]. This observation is consistent with their knockdown known to drive a “full” EMT in both cancer cell lines and in developmental contexts [ 46 , 49 ].…”

Section: Resultsmentioning

confidence: 99%

See 1 more Smart Citation

Hybrid E/M Phenotype(s) and Stemness: A Mechanistic Connection Embedded in Network Topology

Pasani

Sahoo

Jolly

2020

JCM

Self Cite

View full text Add to dashboard Cite

Metastasis remains an unsolved clinical challenge. Two crucial features of metastasizing cancer cells are (a) their ability to dynamically move along the epithelial–hybrid–mesenchymal spectrum and (b) their tumor initiation potential or stemness. With increasing functional characterization of hybrid epithelial/mesenchymal (E/M) phenotypes along the spectrum, recent in vitro and in vivo studies have suggested an increasing association of hybrid E/M phenotypes with stemness. However, the mechanistic underpinnings enabling this association remain unclear. Here, we develop a mechanism-based mathematical modeling framework that interrogates the emergent nonlinear dynamics of the coupled network modules regulating E/M plasticity (miR-200/ZEB) and stemness (LIN28/let-7). Simulating the dynamics of this coupled network across a large ensemble of parameter sets, we observe that hybrid E/M phenotype(s) are more likely to acquire stemness relative to “pure” epithelial or mesenchymal states. We also integrate multiple “phenotypic stability factors” (PSFs) that have been shown to stabilize hybrid E/M phenotypes both in silico and in vitro—such as OVOL1/2, GRHL2, and NRF2—with this network, and demonstrate that the enrichment of hybrid E/M phenotype(s) with stemness is largely conserved in the presence of these PSFs. Thus, our results offer mechanistic insights into recent experimental observations of hybrid E/M phenotype(s) that are essential for tumor initiation and highlight how this feature is embedded in the underlying topology of interconnected EMT (Epithelial-Mesenchymal Transition) and stemness networks.

show abstract

Section: Discussionmentioning

confidence: 73%

Section: Resultsmentioning

confidence: 99%

Hybrid E/M Phenotype(s) and Stemness: A Mechanistic Connection Embedded in Network Topology

Pasani

Sahoo

Jolly

2020

JCM

Self Cite

View full text Add to dashboard Cite

show abstract

“…In the context of cancer, cells with punctate E-CADHERIN localization represent an intermediate epithelial-mesenchymal state ( Sha et al, 2019 ; Yang et al, 2020 ), characterized by an increased propensity for collective invasion and metastasis ( Aiello et al, 2018 ; Ayollo et al, 2009 ; Gloushankova et al, 2017 ; Jolly et al, 2015 ; Kovac et al, 2018 ; Saitoh, 2018 ). This state is linked to the downregulation of the transcription factor Ovol1 ( Jia et al, 2015 ; Saxena et al, 2020 ), which suppresses a mesenchymal identity, and the tight junction component, Claudin7 ( Aiello et al, 2018 ; Kim et al, 2019 ; Wang et al, 2018 ). Both of these factors were also significantly downregulated in Rreb1 -/- embryos ( Figure 6—figure supplement 1A ).…”

Section: Resultsmentioning

confidence: 99%

The transcription factor Rreb1 regulates epithelial architecture, invasiveness, and vasculogenesis in early mouse embryos

Morgani

Nichols

et al. 2021

eLife

View full text Add to dashboard Cite

Ras-responsive element-binding protein 1 (Rreb1) is a zinc-finger transcription factor acting downstream of RAS signaling. Rreb1 has been implicated in cancer and Noonan-like RASopathies. However, little is known about its role in mammalian non-disease states. Here, we show that Rreb1 is essential for mouse embryonic development. Loss of Rreb1 led to a reduction in the expression of vasculogenic factors, cardiovascular defects, and embryonic lethality. During gastrulation, the absence of Rreb1 also resulted in the upregulation of cytoskeleton-associated genes, a change in the organization of F-ACTIN and adherens junctions within the pluripotent epiblast, and perturbed epithelial architecture. Moreover, Rreb1 mutant cells ectopically exited the epiblast epithelium through the underlying basement membrane, paralleling cell behaviors observed during metastasis. Thus, disentangling the function of Rreb1 in development should shed light on its role in cancer and other diseases involving loss of epithelial integrity.

show abstract

“…To address this question we assessed the levels of a panel of five well-studied EMT-inducing or EMT-associated factors – SNAI1, SNAI2, ZEB1, ZEB2, and TWIST1 (Subbalakshmi et al 2021; J. Yang et al 2004; Drápela et al 2020; Vandewalle 2005) – and five MET-inducing or MET-associated factors – GRHL2, OVOL1, OVOL2, ESRP1, and ESRP2 (Saxena et al 2020; Cieply et al 2012; Jolly et al 2018; Jeong et al 2017; Fici et al 2017) – across tumor types.…”

Section: Resultsmentioning

confidence: 99%

Analysis of immune subtypes across the epithelial-mesenchymal plasticity spectrum

Chakraborty

Chen

McMullen

et al. 2021

Preprint

View full text Add to dashboard Cite

Epithelial-mesenchymal plasticity plays a critical role in many solid tumor types as a mediator of metastatic dissemination and treatment resistance. In addition, there is also a growing appreciation that the epithelial/mesenchymal status of a tumor plays a role in immune evasion and immune suppression. A deeper understanding of the immunological features of different tumor types has been facilitated by the availability of large gene expression datasets and the development of methods to deconvolute bulk RNA-Seq data. These resources have generated powerful new ways of characterizing tumors, including classification of immune subtypes based on differential expression of immunological genes. In the present work, we combine scoring algorithms to quantify epithelial-mesenchymal plasticity with immune subtype analysis to understand the relationship between epithelial plasticity and immune subtype across cancers. We find heterogeneity of epithelial-mesenchymal transition (EMT) status both within and between cancer types, with greater heterogeneity in the expression of EMT-related factors than of MET-related factors. We also find that specific immune subtypes have associated EMT scores and differential expression of immune checkpoint markers.

show abstract

OVOL1/2: Drivers of Epithelial Differentiation in Development, Disease, and Reprogramming

Cited by 27 publications

References 68 publications

Hybrid E/M Phenotype(s) and Stemness: A Mechanistic Connection Embedded in Network Topology

Hybrid E/M Phenotype(s) and Stemness: A Mechanistic Connection Embedded in Network Topology

The transcription factor Rreb1 regulates epithelial architecture, invasiveness, and vasculogenesis in early mouse embryos

Analysis of immune subtypes across the epithelial-mesenchymal plasticity spectrum

Contact Info

Product

Resources

About