ΔNp63-Regulated Epithelial-to-Mesenchymal Transition State Heterogeneity Confers a Leader–Follower Relationship That Drives Collective Invasion

Westcott, Jill M.; Camacho, Sharon; Nasir, Apsra; Huysman, Molly E.; Rahhal, Raneen; Dang, Tuyen T.; Riegel, Anna T.; Brekken, Rolf A.; Pearson, Gray W.

doi:10.1158/0008-5472.can-20-0014

Cited by 19 publications

(48 citation statements)

References 63 publications

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“…To understand how a trailblazer state is induced we investigated the invasive properties of C3TAg tumor organoids. Consistent with previous observations (21,32), there was heterogeneity in the invasive behavior of organoids derived from C3TAg tumors (Fig. 1A) .…”

Section: Resultssupporting

confidence: 92%

“…S1C) , which is detected in opportunist cells derived from human cell lines. DNp63 expressing cells also opportunistically invade in C3TAg tumors and C3TAg tumor explants (21).…”

Section: Resultsmentioning

confidence: 99%

“…Additional cells subsequently invade by following the microtracks created by the lead cell (20). A trailblazer EMT confers cells with an enhanced ability to promote the formation of microtracks (12,21). Notably, cells that promote microtack generation induce the collective invasion of “opportunist” siblings that have not undergone a trailblazer EMT and have a relatively diminished intrinsic invasive ability (12,22,23).…”

Section: Introductionmentioning

confidence: 99%

“…Notably, cells that promote microtack generation induce the collective invasion of “opportunist” siblings that have not undergone a trailblazer EMT and have a relatively diminished intrinsic invasive ability (12,22,23). The interaction between trailblazer and opportunist cells can promote the progression from ductal carcinoma in situ (DCIS) to invasive breast cancer (IBC) in an orthotopic tumor model (21). Consistent with results obtained with these experimental models, the interaction of distinct subpopulations is observed during the initial transition from DCIS to IBC in breast cancer patients (24,25).…”

Section: Introductionmentioning

confidence: 99%

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The integration of Tgfβ and Egfr signaling programs confers the ability to lead heterogeneous collective invasion

Camacho

Nasir

Rahhal

et al. 2020

Preprint

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Cells that lead collective invasion can have distinct traits and regulatory programs compared to the cells that follow them. Notably, a specific type of epithelial-to-mesenchymal transition (EMT) program we term a “trailblazer EMT” endows cells with the ability to lead collective invasion and promote the opportunistic invasion of intrinsically less invasive siblings. Here, we sought to define the regulatory programs that are responsible for inducing a trailblazer EMT in a genetically engineered mouse (GEM) model of breast cancer. Analysis of fresh tumor explants, cultured organoids and cell lines revealed that the trailblazer EMT was controlled by TGFβ pathway activity that induced a hybrid EMT state characterized by cells expressing E-cadherin and Vimentin. Notably, the trailblazer EMT was active in cells lacking keratin 14 expression and evidence of trailblazer EMT activation was detected in collectively invading cells in primary tumors. The trailblazer EMT program required expression of the transcription factor Fra1, which was regulated by the parallel autocrine activation of the epidermal growth factor receptor (EGFR) and extracellular signal regulated kinases (ERK) 1 and 2. Together, these results reveal that the activity of parallel TGFβ and EGFR pathways confers cells with the ability to lead collective invasion through the induction of a trailblazer EMT.

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Section: Resultssupporting

confidence: 92%

“…S1C) , which is detected in opportunist cells derived from human cell lines. DNp63 expressing cells also opportunistically invade in C3TAg tumors and C3TAg tumor explants (21).…”

Section: Resultsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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The integration of Tgfβ and Egfr signaling programs confers the ability to lead heterogeneous collective invasion

Camacho

Nasir

Rahhal

et al. 2020

Preprint

Self Cite

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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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Peroxidasin Enhances Basal Phenotype and Inhibits Branching Morphogenesis in Breast Epithelial Progenitor Cell Line D492

Sigurdardottir

Jonasdottir

Ásbjarnarson

et al. 2021

J Mammary Gland Biol Neoplasia

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The human breast is composed of terminal duct lobular units (TDLUs) that are surrounded by stroma. In the TDLUs, basement membrane separates the stroma from the epithelial compartment, which is divided into an inner layer of luminal epithelial cells and an outer layer of myoepithelial cells. Stem cells and progenitor cells also reside within the epithelium and drive a continuous cycle of gland remodelling that occurs throughout the reproductive period. D492 is an epithelial cell line originally isolated from the stem cell population of the breast and generates both luminal and myoepithelial cells in culture. When D492 cells are embedded into 3D reconstituted basement membrane matrix (3D-rBM) they form branching colonies mimicking the TDLUs of the breast, thereby providing a well-suited in vitro model for studies on branching morphogenesis and breast development. Peroxidasin (PXDN) is a heme-containing peroxidase that crosslinks collagen IV with the formation of sulfilimine bonds. Previous studies indicate that PXDN plays an integral role in basement membrane stabilisation by crosslinking collagen IV and as such contributes to epithelial integrity. Although PXDN has been linked to fibrosis and cancer in some organs there is limited information on its role in development, including in the breast. In this study, we demonstrate expression of PXDN in breast epithelium and stroma and apply the D492 cell line to investigate the role of PXDN in cell differentiation and branching morphogenesis in the human breast. Overexpression of PXDN induced basal phenotype in D492 cells, loss of plasticity and inhibition of epithelial-to-mesenchymal transition as is displayed by complete inhibition of branching morphogenesis in 3D culture. This is supported by results from RNA-sequencing which show significant enrichment in genes involved in epithelial differentiation along with significant negative enrichment of EMT factors. Taken together, we provide evidence for a novel role of PXDN in breast epithelial differentiation and mammary gland development.

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ΔNp63-Regulated Epithelial-to-Mesenchymal Transition State Heterogeneity Confers a Leader–Follower Relationship That Drives Collective Invasion

Cited by 19 publications

References 63 publications

The integration of Tgfβ and Egfr signaling programs confers the ability to lead heterogeneous collective invasion

The integration of Tgfβ and Egfr signaling programs confers the ability to lead heterogeneous collective invasion

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

Peroxidasin Enhances Basal Phenotype and Inhibits Branching Morphogenesis in Breast Epithelial Progenitor Cell Line D492

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