EMT cells increase breast cancer metastasis via paracrine GLI activation in neighbouring tumour cells

Neelakantan, Deepika; Zhou, Hengbo; Oliphant, Michael; Zhang, Xiaomei; Simon, Lukas M.; Henke, David; Shaw, Chad A.; Wu, Meng-Fen; Hilsenbeck, Susan G.; White, Lisa D.; Lewis, Michael T.; Ford, Heide L.

doi:10.1038/ncomms15773

Cited by 147 publications

(157 citation statements)

References 41 publications

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“…ZEB1 can not only enforce its own expression through these loops, but also alter its microenvironment, thus enhancing non-cell autonomous effects of EMT. Similar non-cell autonomous effects can lead to a cooperative behavior between epithelial and mesenchymal cells in establishing metastases [44,63,64]. Moreover, these non-cell autonomous effects of EMT mediated by ZEB1 may help offer a plausible explanation why metastasis can be blunted largely by knockout of ZEB1 [65], but not necessarily by that of SNAIL or TWIST [66].…”

Section: Discussionmentioning

confidence: 98%

Interconnected feedback loops among ESRP1, HAS2, and CD44 regulate epithelial-mesenchymal plasticity in cancer

Jolly

Preca

Tripathi

et al. 2018

Preprint

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Aberrant activation of epithelial-mesenchymal transition (EMT) in carcinoma cells contributes to increased migration and invasion, metastasis, drug resistance, and tumor-initiating capacity. EMT is not always a binary process, rather cells may exhibit a hybrid epithelial/mesenchymal (E/M) phenotype. ZEB1 -a key transcription factor driving EMT -can both induce and maintain a mesenchymal phenotype. Recent studies have identified two novel autocrine feedback loops utilizing ESRP1, HAS2, and CD44 that maintain high levels of ZEB1. However, how the crosstalk between these feedback loops alters the dynamics of epithelial-hybrid-mesenchymal transition remains elusive. Here, using an integrated theoretical-experimental framework, we identify that these feedback loops can enable cells to stably maintain a hybrid E/M phenotype. Moreover, computational analysis identifies the regulation of ESRP1 as a crucial node, a prediction that is validated by two complementary experiments showing that (a) overexpression of ESRP1 reverts EMT in MCF10A cells treated with TGFβ for 21 days, and (b) knockdown of ESRP1 in stable hybrid E/M H1975 cells drives EMT. Finally, in multiple breast cancer datasets, high levels of ESRP1, ESRP1/HAS2, and ESRP1/ZEB1 correlates with poor prognosis, supporting the relevance of ZEB1/ESRP1 and ZEB1/HAS2 axes in tumor progression. Together, our results unravel how these interconnected feedback loops act in concert to regulate ZEB1 levels and to drive the dynamics of epithelial-hybrid-mesenchymal transition.

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Section: Discussionmentioning

confidence: 98%

Interconnected feedback loops among ESRP1, HAS2, and CD44 regulate epithelial-mesenchymal plasticity in cancer

Jolly

Preca

Tripathi

et al. 2018

Preprint

View full text Add to dashboard Cite

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“…Hybrid E / M cells play a key role in the collective dissemination of tumor cells as clusters, an aggressive mechanism of cancer metastasis (Jolly et al, 2015). Further, EMP-associated phenotypes differ in their tumor-seeding abilities (Grosse-Wilde et al, 2018;Neelakantan et al, 2017) and in their sensitivity to drugs (Creighton et al, 2009;Tièche et al, 2018). Understanding the mechanisms driving EMP will thus be a critical step in the development of more effective anti-cancer therapies.…”

Section: Introductionmentioning

confidence: 99%

A Mechanism for Epithelial-Mesenchymal Heterogeneity in a Population of Cancer Cells

Tripathi

Levine

Jolly

2019

Preprint

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Epithelial-mesenchymal heterogeneity, wherein cells within the same tumor can exhibit an epithelial, a mesenchymal, or one or more hybrid epithelial-mesenchymal phenotype(s), has been observed across cancer types and implicated in metastatic aggressiveness. Here, we have used computational modeling to show that this heterogeneity can emerge from the noise in the partitioning of RNAs and proteins among the daughter cells during cancer cell division. Our model captures the population-level behavior of murine prostate cancer cells, the hysteresis in the dynamics of epithelial-mesenchymal plasticity, and how hybrid phenotype-promoting factors alter the phenotypic composition of a population. We further used the model to describe the implications of heterogeneity for therapeutics. By linking the dynamics of an intracellular regulatory circuit to the phenotypic composition of a population, the study contributes towards understanding how non-genetic heterogeneity can be generated and propagated from a small, homogeneous population, and towards therapeutic targeting of cancer cell heterogeneity.

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“…Understanding the molecular mechanisms that regulate the EMT process is crucial for improving breast carcinoma treatment [22, 23]. Our study showed that ectopic expression of miR-212-5p in TNBC cells impaired their invasion, proliferation and growth.…”

Section: Discussionmentioning

confidence: 95%

MiR-212-5p Suppresses the Epithelial-Mesenchymal Transition in Triple-Negative Breast Cancer by Targeting Prrx2

Yang

Liu

et al. 2017

Cell Physiol Biochem

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Background/Aims: Triple-negative breast cancer (TNBC) is the most aggressive breast cancer subtype. Our study investigated the functional role of miR-212-5p in TNBC. Methods: Realtime PCR was used to quantify miR-212-5p expression levels in 30 paired TNBC samples and adjacent normal tissues. Wound healing and Transwell assays were used to evaluate the effects of miR-212-5p expression on the invasiveness of TNBC cells. Luciferase reporter and Western blot assays were used to verify whether the mRNA encoding Prrx2 is a major target of miR-212-5p. Results: MiR-212-5p was downregulated in TNBC, and its expression levels were related to tumor size, lymph node status and vascular invasion in breast cancer. We also observed that the miR-212-5p expression level was significantly correlated with a better prognosis in TNBC. Ectopic expression of miR-212-5p induced upregulation of E-cadherin expression and downregulation of vimentin expression. The expression of miR212-5p also suppressed the migration and invasion capacity of mesenchymal-like cancer cells accompanied by a morphological shift towards the epithelial phenotype. Moreover, our study observed that miR-212-5p overexpression significantly suppressed Prrx2 by targeting its 3’-untranslated region (3’-UTR) region, and Prrx2 overexpression partially abrogated miR-212-5p-mediated suppression. Conclusions: Our study demonstrated that miR-212-5p inhibits TNBC from acquiring the EMT phenotype by downregulating Prrx2, thereby inhibiting cell migration and invasion during cancer progression.

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EMT cells increase breast cancer metastasis via paracrine GLI activation in neighbouring tumour cells

Cited by 147 publications

References 41 publications

Interconnected feedback loops among ESRP1, HAS2, and CD44 regulate epithelial-mesenchymal plasticity in cancer

Interconnected feedback loops among ESRP1, HAS2, and CD44 regulate epithelial-mesenchymal plasticity in cancer

A Mechanism for Epithelial-Mesenchymal Heterogeneity in a Population of Cancer Cells

MiR-212-5p Suppresses the Epithelial-Mesenchymal Transition in Triple-Negative Breast Cancer by Targeting Prrx2

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