scholarly journals Altered Epithelial-mesenchymal Plasticity as a Result of Ovol2 Deletion Minimally Impacts the Self-renewal of Adult Mammary Basal Epithelial Cells

Author(s):  
Peng Sun ◽  
Yingying Han ◽  
Maksim Plikus ◽  
Xing Dai

AbstractStem-cell containing mammary basal epithelial cells exist in a quasi-mesenchymal transcriptional state characterized by simultaneous expression of typical epithelial genes and typical mesenchymal genes. Whether robust maintenance of such a transcriptional state is required for adult basal stem cells to fuel self-renewal and regeneration remains unclear. In this work, we utilized SMA-CreER to direct efficient basal cell-specific deletion of Ovol2, which encodes a transcription factor that inhibits epithelial-to-mesenchymal transition (EMT), in adult mammary gland. We identified a basal cell-intrinsic role of Ovol2 in promoting epithelial, and suppressing mesenchymal, molecular traits. Interestingly, Ovol2-deficient basal cells display minimal perturbations in their ability to support tissue homeostasis, colony formation, and transplant outgrowth. These findings underscore the ability of adult mammary basal cells to tolerate molecular perturbations associated with altered epithelia-mesenchymal plasticity without drastically compromising their self-renewal potential.

2019 ◽  
Author(s):  
Xue Wang ◽  
Haibo Xu ◽  
Chaping Cheng ◽  
Zhongzhong Ji ◽  
Huifang Zhao ◽  
...  

AbstractThe basal cell compartment in many epithelial tissues such as the prostate, bladder, and mammary gland are generally believed to serve as an important pool of stem cells. However, basal cells are heterogenous and the stem cell subpopulation within basal cells is not well elucidated. Here we uncover that the core epithelial-to-mesenchymal transition (EMT) inducer Zeb is exclusively expressed in a prostate basal cell subpopulation based on both immunocytochemical and cell lineage tracing analysis. The Zeb1+prostate epithelial cells are multipotent prostate basal stem cells (PBSCs) that can self-renew and generate functional prostatic glandular structures with all three epithelial cell types at the single-cell level. Genetic ablation studies reveal an indispensable role for Zeb1 in prostate basal cell development. Utilizing unbiased single cell transcriptomic analysis of over 9000 mouse prostate basal cells, we find that Zeb1+basal cell subset shares gene expression signatures with both epithelial and mesenchymal cells and stands out uniquely among all the basal cell clusters. Moreover, Zeb1+epithelial cells can be detected in mouse and clinical samples of prostate tumors. Identification of the PBSC and its transcriptome profile is crucial to advance our understanding of prostate development and tumorigenesis.


2012 ◽  
Vol 2012 ◽  
pp. 1-6 ◽  
Author(s):  
Nicolas Pallet ◽  
Eric Thervet ◽  
Dany Anglicheau

Tubular epithelial cells play a central role in the pathogenesis of chronic nephropathies. Previous toxicogenomic studies have demonstrated that cyclosporine- (CsA-) induced epithelial phenotypic changes (EPCs) are reminiscent of an incomplete epithelial to mesenchymal transition (EMT) in a TGF-β-independent manner. Furthermore, we identified endoplasmic reticulum (ER) stress as a potential mechanism that may participate in the modulation of tubular cell plasticity during CsA exposure. Because c-jun-N-terminal kinase (JNK), which is activated during ER stress, is implicated in kidney fibrogenesis, we undertook the current study to identify the role of JNK signaling in EPCs induced by CsA. In primary cultures of human renal epithelial cells, CsA activates JNK signaling, and the treatment with a JNK inhibitor reduces the occurrence of cell shape changes, E-cadherin downregulation, cell migration, and Snail-1 expression. Our results suggest that CsA activates JNK signaling, which, in turn, may participate in the morphological alterations through the regulation of Snail-1 expression.


Blood ◽  
2020 ◽  
Vol 136 (8) ◽  
pp. 957-973 ◽  
Author(s):  
Catherine L. Carmichael ◽  
Jueqiong Wang ◽  
Thao Nguyen ◽  
Oluseyi Kolawole ◽  
Aissa Benyoucef ◽  
...  

Abstract Modulators of epithelial-to-mesenchymal transition (EMT) have recently emerged as novel players in the field of leukemia biology. The mechanisms by which EMT modulators contribute to leukemia pathogenesis, however, remain to be elucidated. Here we show that overexpression of SNAI1, a key modulator of EMT, is a pathologically relevant event in human acute myeloid leukemia (AML) that contributes to impaired differentiation, enhanced self-renewal, and proliferation of immature myeloid cells. We demonstrate that ectopic expression of Snai1 in hematopoietic cells predisposes mice to AML development. This effect is mediated by interaction with the histone demethylase KDM1A/LSD1. Our data shed new light on the role of SNAI1 in leukemia development and identify a novel mechanism of LSD1 corruption in cancer. This is particularly pertinent given the current interest surrounding the use of LSD1 inhibitors in the treatment of multiple different malignancies, including AML.


2019 ◽  
Vol 244 (16) ◽  
pp. 1419-1429
Author(s):  
Shirley Jusino ◽  
Harold I Saavedra

The epithelial-to-mesenchymal transition (EMT) is a complex cellular process in which epithelial cells acquire mesenchymal properties. EMT occurs in three biological settings: development, wound healing and fibrosis, and tumor progression. Despite occurring in three independent biological settings, EMT signaling shares some molecular mechanisms that allow epithelial cells to de-differentiate and acquire mesenchymal characteristics that confer cells invasive and migratory capacity to distant sites. Here we summarize the molecular mechanism that delineates EMT and we will focus on the role of E2 promoter binding factors (E2Fs) in EMT during tumor progression. Since the E2Fs are presently undruggable due to their control in numerous pivotal cellular functions and due to the lack of selectivity against individual E2Fs, we will also discuss the role of three mitotic regulators and/or mitotic kinases controlled by the E2Fs (NEK2, Mps1/TTK, and SGO1) in EMT that can be useful as drug targets. Impact statement The study of the epithelial to mesenchymal transition (EMT) is an active area of research since it is one of the early intermediates to invasion and metastasis—a state of the cancer cells that ultimately kills many cancer patients. We will present in this review that besides their canonical roles as regulators of proliferation, unregulated expression of the E2F transcription factors may contribute to cancer initiation and progression to metastasis by signaling centrosome amplification, chromosome instability, and EMT. Since our discovery that the E2F activators control centrosome amplification and mitosis in cancer cells, we have identified centrosome and mitotic regulators that may represent actionable targets against EMT and metastasis in cancer cells. This is impactful to all of the cancer patients in which the Cdk/Rb/E2F pathway is deregulated, which has been estimated to be most cancer patients with solid tumors.


2019 ◽  
Author(s):  
Justin Parreno ◽  
Michael B. Amadeo ◽  
Elizabeth H. Kwon ◽  
Velia M. Fowler

AbstractPurposeEpithelial to mesenchymal transition (EMT) is a cause of anterior and posterior subcapsular cataracts. Central to EMT is the formation of actin stress fibers. Targeting specific, stress fiber associated tropomyosin in epithelial cells may be a means to prevent stress fiber formation and repress lens EMT.MethodsWe identified Tpm isoforms in mouse immortalized lens epithelial cells and isolated whole lenses by semi-quantitative PCR followed Sanger sequencing. We focused on the role of one particular tropomyosin isoform, Tpm3.1, in EMT. To stimulate EMT, we cultured cells or native lenses in TGFβ2. To test the function of Tpm3.1, we exposed cells or whole lenses to a Tpm3.1-specific chemical inhibitor, TR100, as well as investigated lenses from Tpm3.1 knockout mice. We examined stress fiber formation by confocal microscopy and assessed EMT progression by αsma mRNA (qPCR) and protein (WES immunoassay) analysis.ResultsLens epithelial cells express eight tropomyosin isoforms. Cell culture studies showed that TGFβ2 treatment results in an upregulation of Tpm3.1, which associates with actin in stress fibers. TR100 prevents stress fiber formation and reduces αsma in TGFβ2 treated cells. We confirmed the role of Tpm3.1 in lens epithelial cells in the native lens ex vivo. Culture of whole lenses in the presence of TGFβ2 results in stress fiber formation at the basal regions of epithelial cells. Knockout of Tpm3.1 or treatment of lenses with TR100 prevents basal stress fiber formation and reduces epithelial αsma levels.ConclusionTargeting specific stress fiber associated tropomyosin isoform, Tpm3.1, is a means to represses lens EMT.


2019 ◽  
Vol 63 (5) ◽  
pp. 579-594 ◽  
Author(s):  
Guillem Lambies ◽  
Antonio García de Herreros ◽  
Víctor M. Díaz

Abstract Cell migration is a multifactorial/multistep process that requires the concerted action of growth and transcriptional factors, motor proteins, extracellular matrix remodeling and proteases. In this review, we focus on the role of transcription factors modulating Epithelial-to-Mesenchymal Transition (EMT-TFs), a fundamental process supporting both physiological and pathological cell migration. These EMT-TFs (Snail1/2, Twist1/2 and Zeb1/2) are labile proteins which should be stabilized to initiate EMT and provide full migratory and invasive properties. We present here a family of enzymes, the deubiquitinases (DUBs) which have a crucial role in counteracting polyubiquitination and proteasomal degradation of EMT-TFs after their induction by TGFβ, inflammatory cytokines and hypoxia. We also describe the DUBs promoting the stabilization of Smads, TGFβ receptors and other key proteins involved in transduction pathways controlling EMT.


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