ΔNp63γ/SRC/Slug Signaling Axis Promotes Epithelial-to-Mesenchymal Transition in Squamous Cancers

Srivastava, Kirtiman; Pickard, Adam; Craig, Stephanie G.; Quinn, Gerard P.; Lambe, Shauna M.; James, Jacqueline; McDade, Simon S.; McCance, Dennis J.

doi:10.1158/1078-0432.ccr-17-3775

Cited by 25 publications

(24 citation statements)

References 47 publications

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“…The effect of SLUG on EMP dynamics can also be influenced by upstream regulators of SLUG such as RNF8, YAP, C/EBPδ, miR-151, CBP, RCP, HDAC1, HDAC3, BRD4 and STAT3 [Cheng et al, 2020;Chesnelong et al, 2019;Kuang et al, 2020;Wang et al, 2020;Daugaard et al, 2017;Jury et al, 2020;Dai et al, 2020;Hwang et al, 2017;Hu et al, 2020;Shafran et al, 2020]. Moreover, SLUG may be involved in feedback loops with one or more p63 isoforms [Srivastava et al, 2018;Dang et al, 2016;Herfs et al, 2010] that can also enable a partial EMT [Jolly et al, 2017a;Westcott et al, 2020]. Thus, while the proposed role of SLUG in stabilizing hybrid E/M phenotype(s) is largely robust to parametric variations, including other links and/or nodes at can alter the landscape of EMP dynamics.…”

Section: Discussionmentioning

confidence: 99%

A computational systems biology approach identifies SLUG as a mediator of partial Epithelial-Mesenchymal Transition (EMT)

Subbalakshmi

Sahoo

Biswas

et al. 2020

Preprint

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Epithelial-mesenchymal plasticity comprises of reversible transitions among epithelial, hybrid epithelial/mesenchymal (E/M) and mesenchymal phenotypes, and underlies various aspects of aggressive tumor progression such as metastasis, therapy resistance and immune evasion. The process of cells attaining one or more hybrid E/M phenotypes is termed as partial EMT. Cells in hybrid E/M phenotype(s) can be more aggressive than those in either fully epithelial or mesenchymal state. Thus, identifying regulators of hybrid E/M phenotypes is essential to decipher the rheostats of phenotypic plasticity and consequent accelerators of metastasis. Here, using a computational systems biology approach, we demonstrate that SLUG (SNAIL2) – an EMT-inducing transcription factor – can inhibit cells from undergoing a complete EMT and thus stabilizing them in hybrid E/M phenotype(s). It expands the parametric range enabling the existence of a hybrid E/M phenotype, thereby behaving as a phenotypic stability factor (PSF). Our simulations suggest that this specific property of SLUG emerges from the topology of the regulatory network it forms with other key regulators of epithelial-mesenchymal plasticity. Clinical data suggests that SLUG associates with worse patient prognosis across multiple carcinomas. Together, our results indicate that SLUG can stabilize hybrid E/M phenotype(s).

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Section: Discussionmentioning

confidence: 99%

A computational systems biology approach identifies SLUG as a mediator of partial Epithelial-Mesenchymal Transition (EMT)

Subbalakshmi

Sahoo

Biswas

et al. 2020

Preprint

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“…It was recently shown that the oncoprotein Src in endosomal membranes promoted exosome secretion and tumor progression [186]. Consistently, Src promotes EMT triggered by multiple EMT inducers including EGF [187], leptin [188], Cten [189], and δNp63γ [190]. Anti-EMT strategies involving targeting the TGFβ receptor or CDK2 may inhibit exosome/oncosome release from cancer cells [36].…”

Section: Exosomal Drug Resistancementioning

confidence: 93%

A Novel Model of Cancer Drug Resistance: Oncosomal Release of Cytotoxic and Antibody-Based Drugs

Eguchi

Taha

Calderwood

et al. 2020

Biology

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Extracellular vesicles (EVs), such as exosomes or oncosomes, often carry oncogenic molecules derived from tumor cells. In addition, accumulating evidence indicates that tumor cells can eject anti-cancer drugs such as chemotherapeutics and targeted drugs within EVs, a novel mechanism of drug resistance. The EV-releasing drug resistance phenotype is often coupled with cellular dedifferentiation and transformation in cells undergoing epithelial-mesenchymal transition (EMT), and the adoption of a cancer stem cell phenotype. The release of EVs is also involved in immunosuppression. Herein, we address different aspects by which EVs modulate the tumor microenvironment to become resistant to anticancer and antibody-based drugs, as well as the concept of the resistance-associated secretory phenotype (RASP).

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“…In the context of wound healing, ΔNp63α upregulates the TGF-β pathway through activation of its effectors, SMAD4 and TGF-βR2, thereby facilitating the EMT features of invasion and motility [103] In addition, silencing of the p63-regulated chromatin organizer Satb1 in SCC cells has also been shown to reverse the expression of EMT markers [104]. In another example of the importance of the relative balance of p63 isoforms, ∆Np63γ, but not ∆Np63α, can promote EMT in association with SRC-dependent transcription of Slug in HNSCC cells [105]. Overall, based on these observations, it is likely that ∆Np63α plays a critical role in EMT depending on the cell type, stage of cancer, and balance of other p63 isoforms.…”

Section: Dysregulated δNp63α Disrupts An Extensive Network Of Molementioning

confidence: 99%

Molecular Mechanisms of p63-Mediated Squamous Cancer Pathogenesis

Moses

George

Sakakibara

et al. 2019

IJMS

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The p63 gene is a member of the p53/p63/p73 family of transcription factors and plays a critical role in development and homeostasis of squamous epithelium. p63 is transcribed as multiple isoforms; ΔNp63α, the predominant p63 isoform in stratified squamous epithelium, is localized to the basal cells and is overexpressed in squamous cell cancers of multiple organ sites, including skin, head and neck, and lung. Further, p63 is considered a stem cell marker, and within the epidermis, ΔNp63α directs lineage commitment. ΔNp63α has been implicated in numerous processes of skin biology that impact normal epidermal homeostasis and can contribute to squamous cancer pathogenesis by supporting proliferation and survival with roles in blocking terminal differentiation, apoptosis, and senescence, and influencing adhesion and migration. ΔNp63α overexpression may also influence the tissue microenvironment through remodeling of the extracellular matrix and vasculature, as well as by enhancing cytokine and chemokine secretion to recruit pro-inflammatory infiltrate. This review focuses on the role of ΔNp63α in normal epidermal biology and how dysregulation can contribute to cutaneous squamous cancer development, drawing from knowledge also gained by squamous cancers from other organ sites that share p63 overexpression as a defining feature.

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ΔNp63γ/SRC/Slug Signaling Axis Promotes Epithelial-to-Mesenchymal Transition in Squamous Cancers

Cited by 25 publications

References 47 publications

A computational systems biology approach identifies SLUG as a mediator of partial Epithelial-Mesenchymal Transition (EMT)

A computational systems biology approach identifies SLUG as a mediator of partial Epithelial-Mesenchymal Transition (EMT)

A Novel Model of Cancer Drug Resistance: Oncosomal Release of Cytotoxic and Antibody-Based Drugs

Molecular Mechanisms of p63-Mediated Squamous Cancer Pathogenesis

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